Abstract

OBJECTIVE: To investigate associations in toddlers born extremely preterm (<28weeks) between neonatal neuroimaging and 18- to 22-month developmental and behavioral outcomes.STUDY DESIGN: Cohort analysis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial Neuroimaging and Neurodevelopmental Outcomes Study of infants born extremely preterm. Subjects underwent cranial ultrasonography and near-term magnetic resonance imaging (MRI). At 18-22 months of corrected age, the assessment included the Brief Infant Toddler Social Emotional Assessment (BITSEA) Problem and Competence Scale scores and the Bayley Scales of Infant Development, Third Edition (Bayley-III). The BITSEA Problem Scale assesses dysregulation; the Competence Scale assesses social-emotional competence. We examined associations of Problem and Competence scores and positive screen rates with cranial ultrasonography and near-term MRI. Mean BITSEA and Bayley-III scores were compared using ANOVA and positive screen rates with the chi2 test. We computed correlations between BITSEA and Bayley-III scores.RESULTS: Of the 397 children, positive BITSEA screens were found in 34% for the Problem score and 26% for the Competence score. Presence of lesions on near-term MRI that included cerebellar lesions were significantly associated with lower BITSEA Competence but not with Problem scores; Competence scores were inversely related to the presence/significance of lesions. Positive screens on Competence scores and on both Competence and Problem scores were significantly associated with Bayley-III cognitive and language scores <85 (P

Abstract

We aimed to compare the rates of "surfactant treated respiratory disease" and other neonatal morbidities among moderately preterm (MPT) infants exposed to no, partial, or a complete course of antenatal corticosteroids (ANS).This observational cohort study evaluated MPT infants (290/7-336/7 weeks' gestational age), born between January 2012 and November 2013 and enrolled in the "MPT Registry" of the National Institute of Child Health and Human Development Neonatal Research Network.Data were available for 5,886 infants, including 676 with no exposure, 1225 with partial, and 3,985 with a complete course of ANS. Among no, partial, and complete ANS groups, respectively, there were significant differences in rates of delivery room resuscitation (4.1, 1.4, and 1.2%), surfactant-treated respiratory disease (26.5, 26.3, and 20%), and severe intracranial hemorrhage (3, 2, and 0.8%). Complete ANS course was associated with lower surfactant-treated respiratory disease, compared with partial ANS (odds ratio [OR] 0.62; 95% confidence interval [CI] 0.52-0.74), and no ANS groups (OR 0.52; 95% CI 0.41-0.66) on adjusted analysis.In MPT infants, ANS exposure is associated with lower delivery room resuscitation, surfactant-treated respiratory disease, and severe intracranial hemorrhage; with the lowest frequency of morbidities associated with a complete course.

Abstract

Near-infrared spectroscopy (NIRS) monitoring provides a noninvasive, bedside measure of cerebral and somatic oxygenation in neonates at risk for hemodynamic instability and brain injury. This technology has been increasingly utilized in the neonatal intensive care unit, however clinicians perceive a lack of evidence for the added value of NIRS monitoring. We present six clinical scenarios illustrating the value of NIRS monitoring for the diagnosis and management of critically ill newborns.

Abstract

OBJECTIVE: To identify rates of overweight (body mass index [BMI] 85th percentile) and obesity (BMI 95th percentile) at 6-7 years of age and associated risk factors among extremely preterm infants born at<28 weeks of gestation.STUDY DESIGN: Anthropometrics, blood pressure, and active and sedentary activity levels were prospectively assessed. Three groups were compared, those with a BMI 85th percentile (overweight or obese for age, height, and sex) and 95th percentile (obese) vs <85th percentile. Multiple regression analyses estimated the relative risks of BMI 85th percentile and 95th percentile associated with perinatal and early childhood factors.RESULTS: Of 388 children, 22% had a BMI of 85th percentile and 10% were obese. Children with obesity and overweight compared with normal weight children had higher body fat (subscapular skinfold and triceps skinfold >85th percentile), central fat (waist circumference >90th percentile), spent more time in sedentary activity (20.5 vs 18.2 vs 16.7 hours/week), and had either systolic and/or diastolic hypertension (24% vs 26% vs 14%), respectively. Postdischarge weight gain velocities from 36 weeks postmenstrual age to 18 months, and 18 months to 6-7 years were independently associated with a BMI of 85th percentile, whereas weight gain velocity from 18 months to 6-7 years was associated with obesity.CONCLUSIONS: One in 5 former extremely preterm infants is overweight or obese and has central obesity at early school age. Postdischarge weight gain velocities were associated with overweight and obesity. These findings suggest the obesity epidemic is spreading to the most extremely preterm infants.TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063 and NCT0000.

Abstract

BACKGROUND AND OBJECTIVES: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value.METHODS: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors.RESULTS: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0-129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1-6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6-111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging.CONCLUSIONS: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes.

Abstract

OBJECTIVE: To investigate the range of renal near-infrared spectroscopy (NIRS) measures in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) and to determine the association between renal NIRS measures and the development of acute kidney injury (AKI).STUDY DESIGN: A retrospective chart review was conducted of neonates with moderate to severe HIE who received therapeutic hypothermia at a tertiary care center from 2014 to 2016. Neonates had routine continuous NIRS monitoring of cerebral and renal saturation (Rsat) as part of their clinical care for 72hours of cooling and until 24hours after rewarming. The outcome of AKI was defined by an abnormal rate of decline of serum creatinine over the first 5 days of life. Mixed effects models determined the association between renal NIRS measures and AKI over time.RESULTS: Of 38 neonates with HIE undergoing cooling, 15 (39%) developed AKI. Rsat was lower than cerebral saturation during cooling (P75% by 24-48hours predicted AKI with a sensitivity of 79% and specificity of 82% (area under the receiver operating characteristic curve=0.76).CONCLUSIONS: Throughout cooling, neonates with AKI had higher Rsat measures than those without AKI. These differences may reflect lower oxygen extraction by the injured kidney. NIRS monitoring of Rsat may identify neonates with HIE at risk of developing AKI.

Abstract

Oral feeding skills of moderately preterm infants are not mature at birth.To establish the relationship between postmenstrual age at introduction of first oral feeding and attainment of full oral feeding and hospital discharge for moderately preterm infants.Multicenter retrospective analysis of a prospective cohort of moderately preterm infants admitted to a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hospital.6146 infants born at 29-33weeks' gestation from January 2012 to November 2013.Postmenstrual age at full oral feeding and at hospital discharge.The median postmenstrual age at first oral feeding was 33.9weeks (interquartile range 33.1-34.3). For each week earlier at first oral feeding, full oral feeding occurred 4.5days earlier (p<0.0001) and hospital stay was shortened by 3.4days (p<0.0001). Higher birth weight (p<0.0001) and black maternal race (p=0.0001) were associated with younger postmenstrual age at full oral feeding and at discharge.Moderately preterm infants with earlier introduction of oral feeding achieved earlier full oral feeding and hospital discharge.

Abstract

OBJECTIVE: Many critically ill neonates have an existing brain injury or are at risk of neurologic injury. We developed a "NeuroNICU" (neurologic neonatal intensive care unit) to better provide neurologically focused intensive care.STUDY DESIGN: Demographic and clinical variables, services delivered, and patient outcomes were recorded in a prospective database for all neonates admitted to the NeuroNICU between April 23, 2013, and June 25, 2015.RESULTS: In total, 546 neonates were admitted to the NeuroNICU representing 32% of all NICU admissions. The most common admission diagnoses were congenital heart disease (30%), extreme prematurity (18%), seizures (10%), and hypoxic-ischemic encephalopathy (9%). Neuromonitoring was common, with near-infrared spectroscopy used in 69%, amplitude-integrated electroencephalography (EEG) in 45%, and continuous video EEG in 35%. Overall, 43% received neurology or neurosurgery consultation. Death prior to hospital discharge occurred in 11%. Among survivors, 87% were referred for developmental follow-up, and among those with a primary neurologic diagnosis 57% were referred for neurology or neurosurgical follow-up.CONCLUSION: The NeuroNICU-admitted newborns with or at risk of brain injury comprise a high percentage of NICU volume; 38% had primary neurologic diagnoses, whereas 62% had medical diagnoses. We found many opportunities to provide brain focused intensive care, impacting a substantial proportion of newborns in our NICU.

Abstract

To describe the frequency and extent of delivery room resuscitation and evaluate the association of delivery room resuscitation with neonatal outcomes in moderately preterm (MPT) infants.This was an observational cohort study of MPT infants delivered at 290/7 to 336/7 weeks' gestational age (GA) enrolled in the Neonatal Research Network MPT registry. Infants were categorized into 5 groups based on the highest level of delivery room intervention: routine care, oxygen and/or continuous positive airway pressure, bag and mask ventilation, endotracheal intubation, and cardiopulmonary resuscitation including chest compressions and/or epinephrine use. The association of antepartum and intrapartum risk factors and discharge outcomes with the intensity of resuscitation was evaluated.Of 7014 included infants, 1684 (24.0%) received routine care and no additional resuscitation, 2279 (32.5%) received oxygen or continuous positive airway pressure, 1831 (26.1%) received bag and mask ventilation, 1034 (14.7%) underwent endotracheal intubation, and 186 (2.7%) received cardiopulmonary resuscitation. Among the antepartum and intrapartum factors, increasing GA, any exposure to antenatal steroids and prolonged rupture of membranes decreased the likelihood of receipt of all levels of resuscitation. Infants who were small for GA (SGA) had increased risk of delivery room resuscitation. Among the neonatal outcomes, respiratory support at 28 days, days to full oral feeds and length of stay were significantly associated with the intensity of delivery room resuscitation. Higher intensity of resuscitation was associated with increased risk of mortality.The majority of MPT infants receive some level of delivery room resuscitation. Increased intensity of delivery room interventions was associated with prolonged respiratory and nutritional support, increased mortality, and a longer length of stay.

Abstract

To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies.Infants 26 weeks of gestation born between 2002 and 2012 who had cranial imaging studies at least twice, the most abnormal study at <28 days of age and another closest to 36 weeks, were reviewed. The outcome of late death (after 36 weeks postmenstrual age) or neurodevelopmental impairment (NDI) in surviving infants at 18-26 months corrected age was compared between the infants with no cystic periventricular leukomalacia on both studies and cystic periventricular leukomalacia that disappeared (cystic periventricular leukomalacia at <28 days but not at 36 weeks), persisted (cystic periventricular leukomalacia on both studies), or appeared late (cystic periventricular leukomalacia only at 36 weeks). Predictors of NDI were evaluated by logistic regression.Of 7063 eligible infants, 433 (6.1%) had cystic periventricular leukomalacia. Among the 433 infants with cystic periventricular leukomalacia, cystic periventricular leukomalacia disappeared in 76 (18%), persisted in 87 (20%), and 270 (62%) had late cystic periventricular leukomalacia. Loss to follow-up ranged between 3% and 13%. Death or NDI was more common in infants with disappeared cystic periventricular leukomalacia compared with those with no cystic periventricular leukomalacia (38 of 72 [53%] vs 1776 of 6376 [28%]; OR [95% CI] 2.8 [1.8-4.6]). Disappeared, persistent, and late cystic periventricular leukomalacia were all also independently associated with NDI (OR 1.17, 1.21, and 1.16, respectively).Infants with "disappeared" cystic periventricular leukomalacia are at increased risk of adverse outcome similar to infants with persistent or late cystic periventricular leukomalacia.

Abstract

To describe the frequency and findings of cranial imaging in moderately preterm infants (born at 290/7-336/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics.We used data from the Neonatal Research Network Moderately Preterm Registry, including the most severe early (28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age, antenatal steroid use, and center.Among 7021 infants, 4184 (60%) underwent cranial imaging. These infants had lower gestational ages and birth weights and higher rates of small for gestational age, outborn birth, cesarean delivery, neonatal resuscitation, and treatment with surfactant, compared with those without imaging (P

Abstract

Bronchopulmonary dysplasia (BPD) occurs in approximately 40% of infants born at younger than 30 weeks' gestation and is associated with adverse pulmonary and neurodevelopmental outcomes.To test whether administration of inhaled nitric oxide to preterm infants requiring positive pressure respiratory support on postnatal days 5 to 14 improves the rate of survival without BPD.This intent-to-treat study was a randomized clinical trial performed at 33 US and Canadian neonatal intensive care units. Participants included 451 neonates younger than 30 weeks' gestation with birth weight less than 1250 g receiving mechanical ventilation or positive pressure respiratory support on postnatal days 5 to 14. Enrollment spanned from December 23, 2009, to April 23, 2012, and neurodevelopmental outcome studies were completed by April 4, 2014.Placebo (nitrogen) or inhaled nitric oxide initiated at 20 ppm was decreased to 10 ppm between 72 and 96 hours after starting treatment and then to 5 ppm on day 10 or 11. Infants remained on the 5-ppm dose until completion of therapy (24 days).The primary outcome was the rate of survival without BPD at 36 weeks' postmenstrual age (PMA). Secondary outcomes included BPD severity, postnatal corticosteroid use, respiratory support, survival, and neurodevelopmental outcomes at 18 to 24 months' PMA.In total, 222 infants (52.3% male [n=116]) received placebo, and 229 infants (50.2% male [n=115]) received inhaled nitric oxide. Their mean (SD) gestation was 25.6 (1.5) vs 25.6 (1.4) weeks, and their mean (SD) birth weight was 750 (164) vs 724 (160) g. Survival without BPD at 36 weeks' PMA was similar between the placebo and inhaled nitric oxide groups (31.5% [n=70] vs 34.9% [n=80]) (odds ratio, 1.17; 95% CI, 0.79-1.73). Rates for severe BPD (26.6% [55 of 207] vs 20.5% [43 of 210]) and postnatal corticosteroid use for BPD (41.0% [91 of 222] vs 41.5% [95 of 229]) and the mean (SD) days of positive pressure respiratory support (55 [40] vs 54 [42]), oxygen therapy (88 [41] vs 91 [59]), and hospitalization (105 [37] vs 108 [54]) were equivalent between the 2 groups. No differences in the incidence of common morbidities were observed. Respiratory outcomes on discharge to home, at 1 year, and at age 18 to 24 months' PMA and neurodevelopmental assessments at 18 to 24 months' PMA did not differ between groups.Inhaled nitric oxide, initiated at 20 ppm on postnatal days 5 to 14 to high-risk preterm infants and continued for 24 days, appears to be safe but did not improve survival without BPD at 36 weeks' PMA or respiratory and neurodevelopmental outcomes at 18 to 24 months' PMA.clinicaltrials.gov Identifier: NCT00931632.

Abstract

To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.The original study was a multicenter RCT. Eligibility: 34 weeks' gestation, <72h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Abstract

OBJECTIVE: To compare echocardiography (ECHO) findings of patients with congenital diaphragmatic hernia (CDH) who required extracorporeal membrane oxygenation (ECMO) to non-ECMO treated patients.STUDY DESIGN: We reviewed clinical and ECHO data of newborns with CDH born between 2009 and 2016. Exclusions included major anomalies, genetic syndromes, or no ECHO prior to ECMO. Pulmonary hypertension was assessed by ductal shunting and tricuspid regurgitant jet. Speckle tracking echocardiography (STE) assessed function by quantifying deformation.RESULTS: Patients with CDH (15 ECMO and 29 with no ECMO) were analyzed. Most patients had a left CDH (88.6%). Age at ECHO was similar between groups. Outborn status (P=.009) and liver position (P=.009) were associated with need for ECMO. Compared with non-ECMO patients, patients who required ECMO had significantly decreased left and right ventricular function by both conventional and STE measures, as well as decreased right and left ventricular output. The right ventricular eccentricity index was higher in ECMO vs non-ECMO patients (2.2 vs 1.8, P=.02). There was no difference in pulmonary hypertension between CDH groups.CONCLUSIONS: Need for ECMO was associated with decreased left and right ventricular function, as assessed by standard and STE measures. There was no difference in pulmonary hypertension between non ECMO and ECMO patients. Abnormal cardiac function may explain nonresponse to pulmonary vasodilators in patients with CDH. Management strategies to improve cardiac function may reduce the need for ECMO in newborns with CDH.

Abstract

Late-onset sepsis (LOS) is an important cause of death and neurodevelopmental impairment in premature infants. The purpose of this study was to assess overall incidence of LOS, distribution of LOS-causative organisms and center variation in incidence of LOS for extremely premature infants over time.In a retrospective analysis of infants 401-1000 g birth weight and 22-28 6/7 weeks of gestational age born at 12 National Institute of Child Health and Human Development Neonatal Research Network centers in the years 2000-2005 (era 1) or 2006-2011 (era 2) who survived >72 hours, we compared the incidence of LOS and pathogen distribution in the 2 eras using the test. We also examined the effect of birth year on the incidence of LOS using multivariable regression to adjust for nonmodifiable risk factors and for center. To assess whether the incidence of LOS was different among centers in era 2, we used a multivariable regression model to adjust for nonmodifiable risk factors.Ten-thousand one-hundred thirty-one infants were studied. LOS occurred in 2083 of 5031 (41%) infants in era 1 and 1728 of 5100 (34%) infants in era 2 (P < 0.001). Birth year was a significant predictor of LOS on adjusted analysis, with birth years 2000-2009 having a significantly higher odds of LOS than the reference year 2011. Pathogens did not differ, with the exception of decreased fungal infection (P < 0.001). In era 2, 9 centers had significantly higher odds of LOS compared with the center with the lowest incidence.The incidence of LOS decreased over time. Further investigation is warranted to determine which interventions have the greatest impact on infection rates.

Abstract

Hypothermia for 72 hours at 33.5C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high.To determine if cooling for 120 hours or to a temperature of 32.0C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy.Randomized 22 factorial clinical trial in neonates (36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016.A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5C for 72 hours (n=95), 32.0C for 72 hours (n=90), 33.5C for 120 hours (n=96), or 32.0C for 120 hours (n=83).The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification.The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5C and 51 of 162 (31.5%) cooled to 32.0C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P=.048), with primary outcome rates of 29.3% at 33.5C for 72 hours, 34.5% at 32.0C for 72 hours, 34.4% at 33.5C for 120 hours, and 28.2% at 32.0C for 120 hours.Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5C.clinicaltrials.gov Identifier: NCT01192776.

Abstract

BackgroundExtremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the United States; yet these infants are the focus of most published research. Moderately preterm neonates (MPT, 29-33(6/7) weeks) are an understudied group of high-risk infants.MethodsTo determine the neonatal outcomes of MPT infants across the gestational age spectrum, and to compare these with EPT infants. A prospective observational cohort was formed in 18 level 3-4 neonatal intensive care units (NICUs) in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT infants admitted to NICUs and all EPT infants born at sites between January 2012 and November 2013. Antenatal characteristics and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses.ResultsMPT infants experienced morbidities similar to, although at lower rates than, those of EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. Central Nervous System injury occurred, including intraventricular hemorrhage. Most MPT infants required respiratory support, but sequelae such as bronchopulmonary dysplasia were rare. The primary contributors to hospitalization beyond 36 weeks' gestation were inability to achieve adequate oral intake and persistent apnea.ConclusionsMPT infants experience morbidity and prolonged hospitalization. Such morbidity deserves focused research to improve therapeutic and prevention strategies.Pediatric Research advance online publication, 24 May 2017; doi:10.1038/pr.2017.46.

Abstract

ObjectiveThis study tested the effectiveness of a video teaching tool in improving identification and classification of encephalopathy in infants. Study DesignWe developed an innovative video teaching tool to help clinicians improve their skills in interpreting the neonatal neurological examination for grading encephalopathy. Pediatric residents were shown 1-minute video clips demonstrating exam findings in normal neonates and neonates with various degrees of encephalopathy. Findings from five domains were demonstrated: spontaneous activity, level of alertness, posture/tone, reflexes, and autonomic responses. After each clip, subjects were asked to identify whether the exam finding was normal or consistent with mild, moderate, or severe abnormality. Subjects were then directed to a web-based teaching toolkit, containing a compilation of videos demonstrating normal and abnormal findings on the neonatal neurological examination. Immediately after training, subjects underwent posttesting, again identifying exam findings as normal, mild, moderate, or severe abnormality. ResultsResidents improved in their overall ability to identify and classify neonatal encephalopathy after viewing the teaching tool. In particular, the identification of abnormal spontaneous activity, reflexes, and autonomic responses were most improved. ConclusionThis pretest/posttest evaluation of an educational tool demonstrates that after viewing our toolkit, pediatric residents were able to improve their overall ability to detect neonatal encephalopathy.

Abstract

Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 g/kg followed by a continuous infusion of 5 g/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.

Abstract

Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes.We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death.Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively).The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633 .).

Abstract

Unpublished results can bias biomedical literature, favoring positive over negative findings, primary over secondary analyses, and can lead to duplicate studies that unnecessarily endanger subjects and waste resources. The Neonatal Research Network's (NRN) publication policies for approving, reviewing, and tracking abstracts and papers work to combat these problems. In 2003, the NRN restricted investigators with unfinished manuscripts from proposing new ones and in 2010, urged authors to complete long-outstanding manuscripts. Data from 1991 to 2015 were analyzed to determine effectiveness of these policy changes. The NRN has achieved an overall publication rate of 78% for abstracts. For 1990-2002, of 137 abstracts presented, 43 (31%) were published within 2 years; for 2003-2009, after the manuscript completion policy was instituted, of 140 abstracts presented, 68 (49%) were published within 2 years. Following the effort in 2010, the rate increased to 64%. The NRN surpassed reported rates by developing a comprehensive process, holding investigators accountable and tracking abstracts from presentation to publication.

Abstract

The 21st century began with the FDA approval of inhaled nitric oxide therapy for the treatment of neonatal hypoxic respiratory failure associated with pulmonary hypertension in recognition of the 2 randomized clinical trials demostrating a significant reduction in the need for extracorporeal support in the term and near-term infant. Inhaled nitric oxide is one of only a few therapeutic agents approved for use through clinical investigations primarily in the neonate. This article provides an overview of the pertinent biology and chemistry of nitric oxide, discusses potential toxicities, and reviews the results of pertinent clinical investigations and large randomized clinical trials including neurodevelopmental follow-up in term and preterm neonates. The clinical investigations conducted by the Eunice Kennedy Shriver NICHD Neonatal Research Network will be discussed and placed in context with other pertinent clinical investigations exploring the efficacy of inhaled nitric oxide therapy in neonatal hypoxic respiratory failure.

Abstract

To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36weeks postmenstrual age (PMA) and less growth failure at 36weeks PMA and 18-22months corrected age.We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n=402, PMA 261weeks, birth weight 839186g) or higher (91%-95%, n=408, PMA 261weeks, birth weight 840191g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36weeks PMA; and 18-22months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36weeks PMA and 18-22months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression.Growth outcomes including growth at 36weeks PMA and 18-22months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups.Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.

Abstract

To describe inhaled nitric oxide (iNO) exposure in preterm infants and variation in neonatal intensive care unit (NICU) use.This was a retrospective cohort study of infants, 22 to 33+6/7 weeks of gestational age (GA), during 2005 to 2013. Analyses were stratified by GA and included population characteristics, iNO use over time and hospital variation.Of the 65824 infants, 1718 (2.61%) received iNO. Infants, 22 to 24+6/7 weeks of GA, had the highest incidence of iNO exposure (6.54%). Community NICUs (n=77, median hospital use rate 0.7%) used less iNO than regional NICUs (n=23, median hospital use rate 5.8%). In 22 to 24+6/7 weeks of GA infants, the median rate in regional centers was 10.6% (hospital interquartile range 3.8% to 22.6%).iNO exposure varied with GA and hospital level, with the most use in extremely premature infants and regional centers. Variation reflects a lack of consensus regarding the appropriate use of iNO for preterm infants.Journal of Perinatology advance online publication, 31 March 2016; doi:10.1038/jp.2016.49.

Abstract

Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth.Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006-2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected 72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset.Early-onset infections were diagnosed in 389 of 396,586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence.Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated.

Abstract

BackgroundWe previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. ObjectiveThis study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. Study DesignThe previously reported study was a multicenter, prospective cohort study of 647 infants34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. ResultsAll the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. ConclusionsThe definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.

Abstract

ObjectiveThe aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points. DesignWe retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants<1,000g birth weight or<29 weeks' gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS]<28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria. ResultsAbout 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants<26 weeks' gestation versus infants of 26 to 28 weeks' gestation (18.5 vs. 11.5%; p=0.013). ConclusionsCranial imaging at both<28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants.

Abstract

ObjectiveThe aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points. DesignWe retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants<1,000g birth weight or<29 weeks' gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS]<28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria. ResultsAbout 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants<26 weeks' gestation versus infants of 26 to 28 weeks' gestation (18.5 vs. 11.5%; p=0.013). ConclusionsCranial imaging at both<28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants.

Abstract

ObjectiveAmplitude-integrated electroencephalography (aEEG) is a simplified method for continuous monitoring of brain activity in the neonatal intensive care unit (NICU). Our objective was to describe current aEEG use in the United States. Study DesignAn online survey was distributed to the American Academy of Pediatrics Section on Perinatal Pediatrics' list serve. ResultA total of 654 surveys were received; 55% of respondents reported using aEEG. aEEG was utilized more often in academic and levels III and IV NICUs; hypoxic-ischemic encephalopathy and suspected seizures were the most common indications for use. aEEG was primarily interpreted by neonatologists (87%), with approximately half reporting either self-teaching or hospital-based training for interpretation. For those not using aEEG, uncertain clinical benefit (40%) and cost (17%) were reported as barriers to use. ConclusionMore than half of neonatologists utilize aEEG, with practice variation by NICU setting. Barriers to wider adoption include education regarding potential benefit, training, and cost.

Abstract

ObjectiveAmplitude-integrated electroencephalography (aEEG) is a simplified method for continuous monitoring of brain activity in the neonatal intensive care unit (NICU). Our objective was to describe current aEEG use in the United States. Study DesignAn online survey was distributed to the American Academy of Pediatrics Section on Perinatal Pediatrics' list serve. ResultA total of 654 surveys were received; 55% of respondents reported using aEEG. aEEG was utilized more often in academic and levels III and IV NICUs; hypoxic-ischemic encephalopathy and suspected seizures were the most common indications for use. aEEG was primarily interpreted by neonatologists (87%), with approximately half reporting either self-teaching or hospital-based training for interpretation. For those not using aEEG, uncertain clinical benefit (40%) and cost (17%) were reported as barriers to use. ConclusionMore than half of neonatologists utilize aEEG, with practice variation by NICU setting. Barriers to wider adoption include education regarding potential benefit, training, and cost.

Abstract

Objective:Amplitude-integrated electroencephalography (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated.Study Design:Inborn infants 23(0/7) to 28(6/7) weeks gestation or birth weight 401 to 1000g were eligible. Serial, 6-h aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed.Result:A total of 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality.Conclusion:Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.Journal of Perinatology advance online publication, 4 December 2014; doi:10.1038/jp.2014.217.

Abstract

Test the feasibility of using a bedside nurse-reported tool (Proxy-Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures.Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool.We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies.The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity.

Abstract

To determine if temperature regulation is improved during neonatal transport using a servo-regulated cooling device when compared with standard practice.We performed a multicenter, randomized, nonmasked clinical trial in newborns with neonatal encephalopathy cooled during transport to 9 neonatal intensive care units in California. Newborns who met institutional criteria for therapeutic hypothermia were randomly assigned to receive cooling according to usual center practices vs device servo-regulated cooling. The primary outcome was the percentage of temperatures in target range (33-34C) during transport. Secondary outcomes included percentage of newborns reaching target temperature any time during transport, time to target temperature, and percentage of newborns in target range 1hour after cooling initiation.One hundred newborns were enrolled: 49 to control arm and 51 to device arm. Baseline demographics did not differ with the exception of cord pH. For each subject, the percentage of temperatures in the target range was calculated. Infants cooled using the device had a higher percentage of temperatures in target range compared with control infants (median 73% [IQR 17-88] vs 0% [IQR 0-52], P

Abstract

Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

Abstract

Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age.Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors.Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes.Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Abstract

Antenatal magnesium (anteMg) is used for various obstetric indications including fetal neuroprotection. Infants exposed to anteMg may be at risk for respiratory depression and delivery room (DR) resuscitation. The study objective was to compare the risk of acute cardiorespiratory events among preterm infants who were and were not exposed to anteMg.This was a retrospective analysis of prospective data collected in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Generic Database from April 1, 2011, through March 31, 2012. The primary outcome was DR intubation or respiratory support at birth or on day 1 of life. Secondary outcomes were invasive mechanical ventilation, hypotension treatment, neonatal morbidities, and mortality. Logistic regression analysis evaluated the risk of primary outcome after adjustment for covariates.We evaluated 1544 infants <29 weeks' gestational age (1091 in anteMg group and 453 in nonexposed group). Mothers in the anteMg group were more likely to have higher education, pregnancy-induced hypertension, and antenatal corticosteroids, while their infants were younger in gestation and weighed less (P < .05). The primary outcome (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.88-1.65) was similar between groups. Hypotension treatment (OR, 0.70; 95% CI, 0.51-0.97) and invasive mechanical ventilation (OR, 0.54; 95% CI, 0.41-0.72) were significantly less in the anteMg group.Among preterm infants age <29 weeks' gestation, anteMg exposure was not associated with an increase in cardiorespiratory events in the early newborn period. The safety of anteMg as measured by the need for DR intubation or respiratory support on day 1 of life was comparable between groups.

Abstract

Hypothermia at 33.5C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.To determine if longer duration cooling (120 hours), deeper cooling (32.0C), or both are superior to cooling at 33.5C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.A randomized, 22 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.Neonates were assigned to 4 hypothermia groups; 33.5C for 72 hours, 32.0C for 72 hours, 33.5C for 120 hours, and 32.0C for 120 hours.The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5C depth vs 32.0C depth (predefined secondary outcomes).The NICU death rates were 7 of 95 neonates (7%) for the 33.5C for 72 hours group, 13 of 90 neonates (14%) for the 32.0C for 72 hours group, 15 of 96 neonates (16%) for the 33.5C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0C group vs 33.5C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0C group vs 33.5C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.clinicaltrials.gov Identifier: NCT01192776.

Abstract

The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions.Multicenter, prospective cohort study of infants 34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)

Abstract

National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-hour area under the curve (AUC24)/MIC >400. The range of vancomycin trough concentrations that best predicts AUC24 >400 in neonates is not known. This understanding would help clarify target trough concentrations for neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine relationships between trough and AUC24 in study neonates. Monte Carlo simulations were performed to examine the effect of dose, post-menstrual age (PMA), and serum creatinine on trough and AUC24 achievement. A total of 1702 vancomycin concentrations from 249 neonates were available for analysis. The median [interquartile range] PMA was 39 wks [32-42 wks] and weight was 2.9 kg [1.6-3.7kg]. Vancomycin clearance was predicted by weight, PMA, and creatinine. At a trough of 10 mg/L, 89% of study neonates had an AUC24 >400. Monte Carlo simulations demonstrated that troughs ranging from 7-11 mg/L were highly predictive of an AUC24 >400 across a range of PMA, serum creatinine, and vancomycin doses. However, a trough 10 mg/L was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs >20 mg/L. A vancomycin trough of 10 mg/L is likely adequate for most neonates with invasive MRSA infections based on AUC24 considerations. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses will be difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

Abstract

The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, a National Institutes of Health consensus development conference cautioned against use of iNO in preterm infants. This study aims (1) to determine the prevalence and variability in use of iNO in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) before and after the consensus conference and (2) separately, to examine associations between iNO use and severe bronchopulmonary dysplasia (BPD) or death.The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008 to 2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.A total of 4885 infants were assessed between 2008 and 2011; 128 (2.6%) received iNO before day 7, 140 (2.9%) between day 7 and 28, and 47 (1.0%) at >28 days. Center-specific iNO use during 2008 to 2010 ranged from 21.9 to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6 to 1.6% (P<0.001) in 2011. The use of iNO started between day 7 and day 14 was more prevalent among younger infants with more severe courses in week 1 and associated with increased risk of severe BPD or death (odds ratio 2.24; 95% confidence interval 1.23 to 4.07).The variability and total use of iNO decreased in 2011 compared with 2008 to 2010. iNO administration started at day 7 was associated with more severe outcomes compared with infants without iNO exposure.

Abstract

The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions.Multicenter, prospective cohort study of infants 34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)

Abstract

Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP.This was a cohort study of 15,751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP.Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49-1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37-0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36-0.777, P = .0011).The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.

Abstract

The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, a National Institutes of Health consensus development conference cautioned against use of iNO in preterm infants. This study aims (1) to determine the prevalence and variability in use of iNO in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) before and after the consensus conference and (2) separately, to examine associations between iNO use and severe bronchopulmonary dysplasia (BPD) or death.The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008 to 2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.A total of 4885 infants were assessed between 2008 and 2011; 128 (2.6%) received iNO before day 7, 140 (2.9%) between day 7 and 28, and 47 (1.0%) at >28 days. Center-specific iNO use during 2008 to 2010 ranged from 21.9 to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6 to 1.6% (P<0.001) in 2011. The use of iNO started between day 7 and day 14 was more prevalent among younger infants with more severe courses in week 1 and associated with increased risk of severe BPD or death (odds ratio 2.24; 95% confidence interval 1.23 to 4.07).The variability and total use of iNO decreased in 2011 compared with 2008 to 2010. iNO administration started at day 7 was associated with more severe outcomes compared with infants without iNO exposure.

Abstract

Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants.A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months' corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses.Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia).Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006.A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower.Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months' corrected age. The role of general anesthesia is implicated but remains unproven.

Abstract

To explore the early childhood pulmonary outcomes of infants who participated in the National Institute of Child Health and Human Development's Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), using a factorial design that randomized extremely preterm infants to lower vs higher oxygen saturation targets and delivery room continuous positive airway pressure (CPAP) vs intubation/surfactant.The Breathing Outcomes Study, a prospective secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, assessed respiratory morbidity at 6-month intervals from hospital discharge to 18-22months corrected age (CA). Two prespecified primary outcomes-wheezing more than twice per week during the worst 2-week period and cough longer than 3days without a cold-were compared for each randomized intervention.One or more interviews were completed for 918 of the 922 eligibleinfants. The incidences of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between the study arms of either randomized intervention. Infants randomized to lower vs higher oxygen saturation targets had a similar risk of death or respiratory morbidity (except for croup and treatment with oxygen or diuretics at home). Infants randomized to CPAP vs intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs 36.5%; P

Abstract

To characterize the implementation of hypothermia for neonatal hypoxic ischemic encephalopathy (HIE) in a population-based cohort.Using the California Perinatal Quality Care Collaborative and California Perinatal Transport System linked 2010-2012 datasets, we categorized infants 36weeks' gestation with HIE as receiving hypothermia or normothermia. Sociodemographic and clinical factors were compared, and multivariable logistic regression was used to determine factors associated with hypothermia therapy.There were 238 reported encephalopathy cases in 2010, 280 in 2011, and 311 in 2012. Hypothermia therapy use in newborns with HIE increased from 59% to 73% across the study period, mainly occurring in newborns with mild or moderate encephalopathy. A total of 36 centers provided hypothermia and cared for 94% of infants, with the remaining 6% being cared for at one of 25 other centers. Of the centers providing hypothermia, 12 centers performed hypothermia therapy to more than 20 patients during the 3-year study period, and 24 centers cared for <20 patients receiving hypothermia. In-hospital mortality was 13%, which primarily was associated with the severity of encephalopathy.Our findings highlight an opportunity to explore practice-site variation and to develop quality improvement interventions to assure consistent evidence-based care of term infants with HIE and appropriate application of hypothermia therapy for eligible newborns.

Abstract

To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.Retrospective cohort study from 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N = 8683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI; a composite of 1 of developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.Tracheostomies were associated with all neonatal morbidities examined and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without (OR adjusted for center 7.0, 95% CI 5.2-9.5). After adjustment for potential confounders, odds of death or NDI remained higher (OR 3.3, 95% CI 2.4-4.6), but odds of death alone were lower (OR 0.4, 95% CI 0.3-0.7) among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life (aOR 0.5, 95% CI 0.3-0.9).Tracheostomy in preterm infants is associated with adverse developmental outcomes and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.

Abstract

Background:Preterm infants with a PDA are at risk for death or development of BPD. However, PDA treatment remains controversial. We investigated if PDA treatment and other clinical or echocardiographic (ECHO) factors were associated with the development of death or BPD.Methods:We retrospectively studied clinical and ECHO characteristics of preterm infants with birth weight <1500g and ECHO diagnosis of a PDA. Logistic regression and classification and regression tree (CART) analyses were performed to assess variables associated with the combined outcome of death or BPD.Results:Of 187 preterm infants with a PDA, 75% were treated with indomethacin or surgery and 25% were managed conservatively. Death or BPD occurred in 80 (43%). Logistic regression found lower gestational age (OR 0.5), earlier year of birth during the study period (OR 0.9), and larger ductal diameter (OR 4.3) were associated with the decision to treat the PDA, while gestational age was the only variable associated with death or BPD (OR 0.6, 95% CI 0.5-0.8).Conclusion:Only lower gestational age and not PDA treatment or ECHO score was associated with the adverse outcome of death or BPD. Further investigation of PDA management strategies and effects on adverse outcomes of prematurity is needed.Pediatric Research (2013); doi:10.1038/pr.2013.253.

Abstract

Background:Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).Methods:We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-.Results:A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups.Conclusion:Disability was not associated with the APOE genotype in this cohort of HIE survivors.

Abstract

Extracorporeal membrane oxygenation (ECMO) continues to be an important rescue therapy for newborns with a variety of causes of cardio-respiratory failure unresponsive to high-frequency ventilation, surfactant replacement, and inhaled nitric oxide. There are approximately 800 neonatal respiratory ECMO cases reported annually to the Extracorporeal Life Support Organization; venoarterial ECMO has been used in approximately 72% with a cumulative survival of 71% and venovenous has been used in 28% with a survival of 84%. Congenital diaphragmatic hernia is now the most common indication for ECMO. This article reviews the development of the two types of extracorporeal support, venoarterial and venovenous ECMO, and discusses the advantages of each method, the current selection criteria, the procedure, and the clinical management of neonates on ECMO.

Abstract

Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994-2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.Of 52,262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.

Abstract

Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of 15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n=50) in a nine-month-period, with fewer than 20% protocol violations.No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

Abstract

To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birthweight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable.The study population consisted of ELBW infants born between 2002 and 2007 at National Institute of Child Health and Development (NICHD) Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE)

Abstract

To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment.Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02).The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.

Abstract

To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18-22 months corrected age compared with infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation.Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000 and 2005. The study infants were designated into three groups: (1) spontaneous intestinal perforation without necrotizing enterocolitis; (2) surgical necrotizing enterocolitis (Bell's stage III); and (3) neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center.Infants with surgical necrotizing enterocolitis had the highest rate of death before hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared with infants in the spontaneous intestinal perforation group (39.1 and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1 and 53.3%; P<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted odds ratio 2.21, 95% confidence interval (CI): 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9, respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4, respectively).Spontaneous intestinal perforation and surgical necrotizing enterocolitis are associated with a similar increase in the risk of death or neurodevelopmental impairment and neurodevelopmental impairment among extremely low birth weight survivors at 18-22 months corrected age.

Abstract

Difficulties with executive function have been found in preterm children, resulting in difficulties with learning and school performance.This study evaluated the relationship of early working memory as measured by object permanence items to the cognitive and language scores on the Bayley Scales-III in a cohort of children born extremely preterm.Logistic regression models were conducted to compare object permanence scores derived from the Bayley Scales-III by race/ethnicity and maternal education, controlling for medical covariates.Extremely preterm toddlers (526), who were part of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's multi-center study, were evaluated at 18-22 months corrected age.Object permanence scores derived from the Bayley Developmental Scales were compared by race/ethnicity and maternal education, controlling for medical covariates.There were no significant differences in object permanence mastery and scores among the treatment groups after controlling for medical and social variables, including maternal education and race/ethnicity. Males and children with intraventricular hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia were less likely to demonstrate object permanence mastery and had lower object permanence scores. Children who attained object permanence mastery had significantly higher Bayley Scales-III cognitive and language scores after controlling for medical and socio-economic factors.Our measure of object permanence is free of influence from race, ethnic and socio-economic factors. Adding this simple task to current clinical practice could help detect early executive function difficulties in young children.

Abstract

Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low -tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl--tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing.Eighty-eight infants received the study drug and were included in the analyses. The -tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in -tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had -tocopherol levels <0.5 mg/dL.A 50-IU/kg dose of vitamin E raised serum -tocopherol levels, but to consistently achieve -tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Abstract

Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low -tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl--tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing.Eighty-eight infants received the study drug and were included in the analyses. The -tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in -tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had -tocopherol levels <0.5 mg/dL.A 50-IU/kg dose of vitamin E raised serum -tocopherol levels, but to consistently achieve -tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Abstract

OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.

Abstract

OBJECTIVE:Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500g,VLBWs) with and without blood stream infection (BSI) during their birth hospitalization.STUDY DESIGN:Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4 and 6 months after birth with blood drawn 4 to 6 weeks after third dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with BW groups and other confounding factors identified in the primary study.RESULT:In all, 244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody 0.35gml(-1).CONCLUSION:BSI was not associated with reduced odds of World Health Organization-defined protective PCV7 responses in VLBWs.Journal of Perinatology advance online publication, 31 January 2013; doi:10.1038/jp.2013.5.

Abstract

OBJECTIVE:Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.METHODS:Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.RESULTS:A BD was present in 1776 (4.8%) of the 37262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41-3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).CONCLUSIONS:Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.

Abstract

To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.Prospective observational study of infants 23(0/7) to 26(6/7) weeks' gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.

Abstract

To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained 72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for 5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates.Of 34396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047].Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.

Abstract

Low-grade periventricular-intraventricular hemorrhage is a common neurologic morbidity among extremely low-gestational-age neonates, yet the outcomes associated with this morbidity are not fully understood. In a contemporary multicenter cohort, we evaluated the impact of such hemorrhages on early (18-22 month) neurodevelopmental outcomes of extremely premature infants.To compare neurodevelopmental outcomes at 18 to 22 months' corrected age for extremely low-gestational-age infants with low-grade (grade 1 or 2) periventricular-intraventricular hemorrhage with those of infants with either no hemorrhage or severe (grade 3 or 4) hemorrhage demonstrated on cranial ultrasonography.Longitudinal observational study.Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.A total of 1472 infants born at less than 27 weeks' gestational age between January 1, 2006, and December 31, 2008, with ultrasonography results within the first 28 days of life and surviving to 18 to 22 months with complete follow-up assessments were eligible.Low-grade periventricular-intraventricular hemorrhage.Outcomes included cerebral palsy; gross motor functional limitation; cognitive and language scores according to the Bayley Scales of Infant Development, 3rd Edition; and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences.Low-grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared with infants without hemorrhage. Compared with low-grade hemorrhage, severe hemorrhage was associated with decreased adjusted continuous cognitive (, -3.91 [95% CI, -6.41 to -1.42]) and language (, -3.19 [-6.19 to -0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (odds ratio [OR], 1.46 [0.74 to 2.88]) and mild language impairment (OR, 1.35 [0.88 to 2.06]).At 18 to 22 months, the neurodevelopmental outcomes of extremely low-gestational-age infants with low-grade periventricular-intraventricular hemorrhage are not significantly different from those without hemorrhage. Additional study at school age and beyond would be informative.

Abstract

To evaluate cooling practices and neonatal outcomes in the state of California during 2010 using the California Perinatal Quality Care Collaborative and California Perinatal Transport System databases.Database analysis to determine the perinatal and neonatal demographics and outcomes of neonates cooled in transport or after admission to a cooling center.Of the 223 infants receiving therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) in California during 2010, 69% were cooled during transport. Despite the frequent use of cooling in transport, cooling center admission temperature was in the target range (33-34C) in only 62 (44%). Among cooled infants, gestational age was <35 weeks in 10 (4.5%). For outborn and transported infants, chronologic age at the time of cooling initiation was >6 h in 20 (11%). When initiated at the birth hospital, cooling was initiated at <6 h of age in 131 (92.9%).More than half of the infants cooled in transport do not achieve target temperature by the time of arrival at the cooling center. The use of cooling devices may improve temperature regulation on transport.

Abstract

Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices.This substudy of the National Institute of Child Health and Human Development Neonatal Research Network PT trial included 1404 infants treated with a single type of PT device during the first 2412h of treatment. The absolute (primary outcome) and relative decrease in total serum bilirubin (TSB) and other measures were evaluated. For infants treated with one PT type during the 2-week intervention period (n=1223), adjusted outcomes at discharge and 18 to 22 months corrected age were determined.In the first 24h, the adjusted absolute (mean (s.d.)) and relative (%) decrease in TSB (mgdl(-1)) were: light-emitting diodes (LEDs) -2.2 (3), -22%; Spotlights -1.7 (2), -19%; Banks -1.3 (3), -8%; Blankets -0.8 (3), -1%; (P<0.0002). Some findings at 18 to 22 months differed between groups.LEDs achieved the greatest initial absolute reduction in TSB but were similar to Spots in the other performance measures. Long-term effects of PT devices in extremely premature infants deserve rigorous evaluation.

Abstract

Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046).We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

Abstract

The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia.Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age.Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

Abstract

Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low-birth-weight (ELBW; 1000g) infants in our Neonatal Research Network trial, the only large trial of AgPT.ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12 to 36h. The effect of AgPT on outcomes (death, impairment, profound impairment, death or impairment (primary outcome), and death or profound impairment) at 18 to 22 months of corrected age was related to BW stratum (501 to 750g; 751 to 1000g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.Baseline illness severity was well characterized using mechanical ventilation and FiO(2) at 24h age. Among mechanically ventilated infants 750g BW (n=684), a reduction in impairment and in profound impairment was offset by higher mortality (P for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.

Abstract

To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants.This was a cohort study of infants with a birth weight 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes.Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.

Abstract

To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development's Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2).Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.

Abstract

To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.This was a prospective pilot RCT of infants 23-0/7 to 26-6/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. A total of 161 infants (44%) were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study because of the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.This pilot RCT was not feasible because of low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.

Abstract

Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization.Data on infants with birth weight 1.0 kg admitted to 18 large academic tertiary NICUs during 1998-2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months.Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30.Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual "outcome trajectories" and evaluate impact of possible morbidities on outcome.

Abstract

Very low birth weight (VLBW) preterm infants are at risk for impaired cerebral autoregulation with pressure passive blood flow. Fluctuations in cerebral perfusion may occur in infants with a hemodynamically significant patent ductus arteriosus (hsPDA), especially during ductal closure. Our goal was to compare cerebral autoregulation using near-infrared spectroscopy in VLBW infants treated for an hsPDA.This prospective observational study enrolled 28 VLBW infants with an hsPDA diagnosed by echocardiography and 12 control VLBW infants without an hsPDA. Near-infrared spectroscopy cerebral monitoring was applied during conservative treatment, indomethacin treatment, or surgical ligation. A cerebral pressure passivity index (PPI) was calculated, and PPI differences were compared using a mixed-effects regression model. Cranial ultrasound and magnetic resonance imaging data were also assessed.Infants with surgically ligated hsPDAs were more likely to have had a greater PPI within 2 hours following ligation than were those treated with conservative management (P=.04) or indomethacin (P=.0007). These differences resolved by 6 hours after treatment.Cerebral autoregulation was better preserved after indomethacin treatment of an hsPDA compared with surgical ligation. Infants requiring surgical hsPDA ligation may be at increased risk for cerebral pressure passivity in the 6 hours following surgery.

Abstract

We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80).The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.).

Abstract

Therapeutic hypothermia initiated at <6 hours of age reduces death and disability in newborns 36 weeks' gestation with moderate to severe hypoxic ischemic encephalopathy. Given the limited therapeutic window, cooling during transport becomes a necessity. Our goal was to describe the current practice of therapeutic hypothermia during transport used in the state of California. All level III neonatal intensive care units (NICUs) were contacted to identify those units providing therapeutic hypothermia. An electronic questionnaire was sent to obtain basic information. Responses were received from 28 (100%) NICUs performing therapeutic hypothermia; 26 NICUs were cooling newborns and two were in the process of program development. Eighteen (64%) centers had cooled a patient in transport, six had not yet cooled in transport, and two do not plan to cool in transport. All 18 centers use passive cooling, except for two that perform both passive and active cooling, and 17 of 18 centers recommend initiation of cooling at the referral hospital. Reported difficulties include overcooling, undercooling, and bradycardia. Cooling on transport is being performed by majority of NICUs providing therapeutic hypothermia. Clinical protocols and devices for cooling in transport are essential to ensure safety and efficacy.

Abstract

OBJECTIVE: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. DESIGN AND PATIENTS: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. RESULTS: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. CONCLUSIONS: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

Abstract

This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, 1,000 g).BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

Abstract

Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care.To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation.Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10,541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables.Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age.Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]).Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

Abstract

To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants.Infants with birth weights 1000 g (n = 1067) had blood samples collected at birth and on days 3 1, 7 1, 14 3, and 21 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1; IL-8; tumor necrosis factor-; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants.IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-, soluble IL r, macrophage inflammatory protein 1) were found to be altered on days 0-4 in infants who developed CP.CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

Abstract

Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory.Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings.Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92-1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98-1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs 5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74-0.98]) was found.Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.

Abstract

To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables.Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results.

Abstract

To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19).The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.

Abstract

Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004.Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

Abstract

Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen.To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers.Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged 72 hours plus treatment with antibiotic therapy for 5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence.Among 396 586 LBs (2006-2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%).In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.

Abstract

Preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) are at risk for fluctuations in cerebral blood flow, but it is unclear how different hsPDA treatment strategies may affect cerebral oxygenation.To compare regional cerebral oxygen saturation (rSO(2)) as measured by near-infrared spectroscopy (NIRS) in very low birth weight (VLBW) infants with a hsPDA treated with conservative management, indomethacin, or surgical ligation.This prospective observational study enrolled 33 VLBW infants with a hsPDA diagnosed by echocardiogram and 12 control VLBW infants without a hsPDA. Infants had NIRS cerebral monitoring applied prior to conservative treatment, indomethacin, or surgical ligation. Cranial ultrasound and magnetic resonance imaging data were also collected.Infants undergoing surgical ligation had a greater time period with >20% change in rSO(2) from baseline (30%) compared to those receiving indomethacin (7.4%, p = 0.001) or control infants without a hsPDA (2.6%, p = 0.0004). NIRS measures were not associated with abnormal neuroimaging in this small cohort.These findings suggest that infants requiring surgical ligation for a hsPDA are at high risk for significant changes in cerebral oxygenation, whereas those receiving either indomethacin or conservative management maintain relatively stable cerebral oxygenation levels. Additional research is necessary to determine if NIRS monitoring identifies infants with a hsPDA at highest risk for brain injury.

Abstract

To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.A total of 6499 ELBW infants (401-1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n = 414) and without (n = 6085) clinical seizures during the initial hospitalization. Using multivariate logistic regression modeling, we examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables.Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio, 3.15; 95% CI, 2.37-4.19).ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.

Abstract

Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (<1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis.The study involved a prospective observational cohort of infants1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis.Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from 1 of these sources: blood (n=96); cerebrospinal fluid (n=9); urine obtained by catheterization (n=52); or other sterile body fluid (n=10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis.Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.

Abstract

This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at or=24 weeks survive, high rates of morbidity among survivors continue to be observed.

Abstract

The goal was to examine the impact of birth at night, on the weekend, and during July or August (the first months of the academic year) and the impact of resident duty-hour restrictions on mortality and morbidity rates for very low birth weight infants.Outcomes were analyzed for 11,137 infants with birth weights of 501 to 1250 g who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry in 2001-2005. Approximately one-half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessments at 18 to 22 months were completed for 4508 infants. Mortality rate, short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth.There was no effect of the timing of birth on mortality rate and no impact on the risks of short-term morbidities except that the risk of retinopathy of prematurity (stage > or =2) was higher after the introduction of duty-hour restrictions and the risk of retinopathy of prematurity requiring operative treatment was lower for infants born during the late night than during the day. There was no impact of the timing of birth on neurodevelopmental outcome except that the risk of hearing impairment or death was slightly lower among infants born in July or August.In this network, the timing of birth had little effect on the risks of death and morbidity for very low birth weight infants, which suggests that staffing patterns were adequate to provide consistent care.

Abstract

There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants.We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen).A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups.The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

Abstract

Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes.We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant.The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events.A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

Abstract

To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants.Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONs: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

Abstract

Fetal and neonatal inflammation is associated with several morbidities of prematurity. Its relationship to retinopathy of prematurity (ROP) has not been investigated. Our objective was to determine the relationship between cytokine levels and ROP in the first 3 postnatal wks. Data for this study were derived from the NICHD Cytokine Study. Dried blood spots (DBS) were obtained from infants <1000 g on days 0-1, 3 +/- 1, 7 +/- 2, 14 +/- 3, and 21 +/- 3. Infants were classified into three groups-no, mild, and severe ROP. Multiplex Luminex assay was used to quantify 20 cytokines. Temporal profiles of cytokines were evaluated using mixed-effects models after controlling for covariates. Of 1074 infants enrolled, 890 were examined for ROP and 877 included in the analysis. ROP was associated with several clinical characteristics on unadjusted analyses. Eight cytokines remained significantly different across ROP groups in adjusted analyses. IL-6 and IL-17 showed significant effects in early time periods (D0-3); TGF-beta, brain-derived neurotrophic factor (BDNF), and regulated on activation, normal T cell expressed and secreted (RANTES) in later time periods (D7-21) and IL-18, C-reactive protein (CRP), and neurotrophin-4 (NT-4) in both early and later time periods. We conclude that perinatal inflammation may be involved in the pathogenesis of ROP.

Abstract

Preterm infants requiring assisted ventilation are at significant risk of both pulmonary and cerebral injury. Inhaled Nitric Oxide, an effective therapy for pulmonary hypertension and hypoxic respiratory failure in the full term infant, has also been studied in preterm infants. The most recent Cochrane review of preterm infants includes 11 studies and 3,370 participants. The results show a statistically significant reduction in the combined outcome of death or chronic lung disease (CLD) in two studies with routine use of iNO in intubated preterm infants. However, uncertainty remains as a larger study (Kinsella 2006) showed no significant benefit for iNO for this combined outcome. Also, trials that included very ill infants do not demonstrate significant benefit. One trial of iNO treatment at a later postnatal age reported a decrease in the incidence of CLD. The aim of this individual patient meta-analysis is to confirm or refute these potentially conflicting results and to determine the extent to which patient or treatment characteristics may explain the results and/or may predict benefit from inhaled Nitric Oxide in preterm infants.The Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration will perform an individual patient data meta-analysis to answer these important clinical questions. Studies will be included if preterm infants receiving assisted ventilation are randomized to receive inhaled Nitric Oxide or to a control group. The individual patient data provided by the Collaborators will be analyzed on an intention-to-treat basis where possible. Binary outcomes will be analyzed using log-binomial regression models and continuous outcomes will be analyzed using linear fixed effects models. Adjustments for trial differences will be made by including the trial variable in the model specification.Thirteen (13) trials, with a total of 3567 infants are eligible for inclusion in the MAPPiNO systematic review. To date 11 trials (n = 3298, 92% of available patients) have agreed to participate. Funding was successfully granted from Ikaria Inc as an unrestricted grant. A collaborative group was formed in 2006 with data collection commencing in 2007. It is anticipated that data analysis will commence in late 2009 with results being publicly available in 2010.

Abstract

As extremely preterm infant mortality rates have decreased, concerns regarding resource use have intensified. Accurate models for predicting time to hospital discharge could aid in resource planning, family counseling, and stimulate quality-improvement initiatives.To develop, validate, and compare several models for predicting the time to hospital discharge for infants <27 weeks' estimated gestational age, on the basis of time-dependent covariates as well as the presence of 5 key risk factors as predictors.We conducted a retrospective analysis of infants <27 weeks' estimated gestational age who were born between July 2002 and December 2005 and survived to discharge from a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network site. Time to discharge was modeled as continuous (postmenstrual age at discharge) and categorical (early and late discharge) variables. Three linear and logistic regression models with time-dependent covariate inclusion were developed (perinatal factors only, perinatal + early-neonatal factors, and perinatal + early-neonatal + later factors). Models for early and late discharge that used the cumulative presence of 5 key risk factors as predictors were also evaluated. Predictive capabilities were compared by using the coefficient of determination (R(2)) for the linear models and the area under the curve (AUC) of the receiver operating characteristic curve for the logistic models.Data from 2254 infants were included. Prediction of postmenstrual age at discharge was poor. However, models that incorporated later clinical characteristics were more accurate in predicting early or late discharge (AUC: 0.76-0.83 [full models] vs 0.56-0.69 [perinatal factor models]). In simplified key-risk-factors models, the predicted probabilities for early and late discharge compared favorably with the observed rates. Furthermore, the AUC (0.75-0.77) was similar to those of the models that included the full factor set.Prediction of early or late discharge is poor if only perinatal factors are considered, but it improves substantially with knowledge of later-occurring morbidities. Predictive models that use a few key risk factors are comparable to the full models and may offer a clinically applicable strategy.

Abstract

Synchronized nasal intermittent positive-pressure ventilation (SNIPPV) use reduces reintubation rates compared with nasal continuous positive airway pressure (NCPAP). Limited information is available on the outcomes of infants managed with SNIPPV.To compare the outcomes of infants managed with SNIPPV (postextubation or for apnea) to infants not treated with SNIPPV at 2 sites.Clinical retrospective data was used to evaluate the use of SNIPPV in infants

Abstract

We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO (2) response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO (2) of 39 +/- 50 mm Hg versus a mean decrease of 11 +/- 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

Abstract

Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of <70, disabling cerebral palsy, or sensory impairment), total dose (tertiles: <0.9, 0.9-1.9, and >/=1.9 mg/kg), and postmenstrual age at first dose. Separate logistic regression tested effect modification according to bronchopulmonary dysplasia severity (Romagnoli risk > 0.5 as high risk, n = 2336 (99%) for days of life 4-7).Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm.Higher steroid dose was associated with increased neurodevelopmental impairment. There is no "safe" window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

Abstract

It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

Abstract

To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure.The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age).Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity.The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.

Abstract

Congenital diaphragmatic hernia is a significant cause of neonatal mortality. The objective of this study was to evaluate the clinical factors associated with death in infants with congenital diaphragmatic hernia by using a large multicenter data set.This was a prospective cohort study of all liveborn infants with congenital diaphragmatic hernia who were cared for at tertiary referral centers belonging to the Congenital Diaphragmatic Hernia Study Group between 1995 and 2004. Factors thought to influence death included birth weight, Apgar scores, size of defect, and associated anomalies. Survival to hospital discharge, duration of mechanical ventilation, and length of hospital stay were evaluated as end points.A total of 51 centers in 8 countries contributed data on 3062 liveborn infants. The overall survival rate was 69%. Five hundred thirty-eight (18%) patients did not undergo an operation and died. The defect size was the most significant factor that affected outcome; infants with a near absence of the diaphragm had a survival rate of 57% compared with infants having a primary repair with a survival rate of 95%. Infants without agenesis but who required a patch for repair had a survival rate of 79% compared with primary repair.The size of the diaphragmatic defect seems to be the major factor influencing outcome in infants with congenital diaphragmatic hernia. It is likely that the defect size is a surrogate marker for the degree of pulmonary hypoplasia. Future research efforts should be directed to accurately quantitate the degree of pulmonary hypoplasia or defect size antenatally. Experimental therapies can then be targeted to prospectively identify high-risk patients who are more likely to benefit.

Abstract

We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group.Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness.Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43).In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

Abstract

To assess interobserver reliability between 2 central readers of cranial ultrasound scanning (CUS) and accuracy of local, compared with central, interpretations.The study was a retrospective analysis of CUS data from the National Institute of Child Health and Human Development (NICHD) trial of inhaled nitric oxide for premature infants. Interobserver reliability of 2 central readers was assessed with kappa or weighted kappa. Accuracy of local, compared with central, interpretations was assessed by using sensitivity and specificity.CUS from 326 infants had both central reader and local interpretations. Central reader agreement for grade 3/4 intraventricular hemorrhage (IVH), grade 3/4 IVH or periventricular leukomalacia (PVL), grade of IVH, and degree of ventriculomegaly was very good (kappa = 0.84, 0.81, 0.79, and 0.75, respectively). Agreement was poor for lower grade IVH and for PVL alone. Local interpretations were highly accurate for grade 3/4 IVH or PVL (sensitivity, 87%-90%; specificity, 92%-93%), but sensitivity was poor-to-fair for grade 1/2 IVH (48%-68%) and PVL (20%-44%).Our findings demonstrate reliability and accuracy of highly unfavorable CUS findings, but suggest caution when interpreting mild to moderate IVH or white matter injury.

Abstract

Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD).Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO.Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21).Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

Abstract

To report the neurodevelopmental outcome of infants enrolled in a randomized multicenter trial of early inhaled nitric oxide (iNO) in term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension.Neonates born at > or = 34 weeks gestation who required assisted ventilation and had an oxygenation index > or = 15 and < 25 were randomized to an early iNO group or a control group. A comprehensive neurodevelopmental assessment of survivors was performed at age 18 to 24 months.The trial enrolled 299 infants, of which 266 (89%) survived to age 18 to 24 months (136 in the early iNO group and 130 in the control group). Follow-up evaluations were done on 234 (88%) of surviving infants. There were no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO, 27%; control, 25%) and hearing impairment (early iNO, 23%; control, 24%). Mental development index scores were similar in the 2 groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO, 89 +/- 17.7; control, 93.5 +/- 18.4).Early iNO therapy for hypoxic respiratory failure in term and near-term infants is not associated with an increase in neurodevelopmental impairment or hearing loss at 18 to 24 months postnatal age.

Abstract

The identification of the biologic properties of nitric oxide (NO) is one of the key scientific discoveries of the century, but its potential for treating human disease is yet to be fully realized. NO has a basic role in regulating vascular tone of the pulmonary circulation, and recent animal models have suggested a more wide reaching influence on perinatal lung development. In animal models, NO has effects on lung growth, angiogenesis, airway smooth muscle proliferation, vascular remodeling, surfactant function, inflammation, and pulmonary mechanics. However, despite extensive basic science investigation and completion of several large clinical trials, the role of NO in the treatment of the premature infant with respiratory distress syndrome remains unclear. One must conclude that the interaction of lung immaturity, ventilator and oxygen-induced lung injury, and NO biology in the premature newborn is incompletely understood. Clinical trial results of inhaled NO therapy in the premature infant are accumulating, but the results do not suggest a clear-cut advantage for the population at greatest risk for death and disability. Whether trial design, dose, duration of therapy, or other factors are responsible has not been determined. Further research is needed to answer these questions and more clearly define the population of premature infants who may derive benefit from this new therapy.

Abstract

The objective of this study was to evaluate the impact of newer therapies on the highest risk patients with congenital diaphragmatic hernia (CDH), those with agenesis of the diaphragm.CDH remains a significant cause of neonatal mortality. Many novel therapeutic interventions have been used in these infants. Those children with large defects or agenesis of the diaphragm have the highest mortality and morbidity.Twenty centers from 5 countries collected data prospectively on all liveborn infants with CDH over a 10-year period. The treatment and outcomes in these patients were examined. Patients were followed until death or hospital discharge.A total of 1,569 patients with CDH were seen between January 1995 and December 2004 in 20 centers. A total of 218 patients (14%) had diaphragmatic agenesis and underwent repair. The overall survival for all patients was 68%, while survival was 54% in patients with agenesis. When patients with diaphragmatic agenesis from the first 2 years were compared with similar patients from the last 2 years, there was significantly less use of ECMO (75% vs. 52%) and an increased use of inhaled nitric oxide (iNO) (30% vs. 80%). There was a trend toward improved survival in patients with agenesis from 47% in the first 2 years to 59% in the last 2 years. The survivors with diaphragmatic agenesis had prolonged hospital stays compared with patients without agenesis (median, 68 vs. 30 days). For the last 2 years of the study, 36% of the patients with agenesis were discharged on tube feedings and 22% on oxygen therapy.There has been a change in the management of infants with CDH with less frequent use of ECMO and a greater use of iNO in high-risk patients with a potential improvement in survival. However, the mortality, hospital length of stay, and morbidity in agenesis patients remain significant.

Abstract

Despite increasing investigation in the area of cardiovascular instability in preterm infants, huge gaps in knowledge remain. None of the current treatments for hypotension, including the use of inotropic agents, have been well studied in the preterm population, and data regarding safety and efficacy are lacking. Thus, the labeling information regarding the use of inotropes as therapeutic agents in this population is inadequate.This article reviews the current deficiencies in knowledge with respect to measuring and achieving normal organ perfusion; summarizes the clinical, methodological, and ethical issues to consider when designing trials to evaluate medications for hemodynamic instability in the preterm neonate; and proposes 2 possible trial designs. Unanswered questions and potential obstacles for the systematic study of drugs to treat cardiovascular instability in preterm neonates are discussed.The neonatal Cardiology Group was established in 2003 by the US Food and Drug Administration (FDA) and the National Institute of Child Health and Human Development (NICHD) as part of the Newborn Drug Development Initiative. The Cardiology Group conducted a number of teleconferences and one meeting to develop a document addressing gaps in knowledge regarding cardiovascular drugs commonly used in low-birth-weight neonates and possible approaches to investigate these drugs. This work was presented at a workshop cosponsored by the NICHD and the FDA held in March 2004 in Baltimore, Maryland. Information for this article was gathered during this initiative.To develop rational, evidence-based guidelines corroborated by robust scientific data for cardiovascular support in newborns, well-designed and adequately powered pharmacologic studies and clinical trials are needed to evaluate the safety and efficacy of inotropic agents and to determine the short- and long-term effects of these drugs. Trials investigating the currently available and novel therapies for cardiovascular instability in neonates will provide information that can be incorporated into product labeling and a scientific framework for cardiovascular management in critically ill neonates. The Cardiology Group identified and prioritized 2 conditions for investigation of therapeutic options for the management of neonatal cardiovascular instability: (1) cardiovascular instability in preterm neonates; and (2) cardiac dysfunction in neonates after cardiopulmonary bypass surgery. Key research questions in the area of cardiovascular instability in the preterm infant include determining optimal blood pressure (BP) in preterm infants; identifying better measures than BP to determine organ perfusion; optimizing hemodynamic treatments; and clarifying any associations between BP or therapy for low BP and mortality, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, and neurodevelopmental outcome. The Cardiology Group concluded that the study of inotropic agents in neonates using outcomes of importance to patients will require a complicated trial design to address the elements discussed. The group proposed 2 clinical trial designs: (1) a placebo-controlled trial with rescue therapy for symptomatic infants; and (2) a targeted BP trial.This summary is intended to stimulate and assist future research in the area of cardiovascular support for preterm infants.

Abstract

Prenatal corticosteroids have been used in fetuses with congenital diaphragmatic hernia (CDH). We tested the utility of steroids by 2 methods.Mothers carrying fetuses with CDH were randomized to 3 weekly doses of betamethasone or placebo starting at 34 weeks. Patients were followed until death or discharge. In a separate cohort study, the CDH Registry was used to compare infants who received prenatal steroids to those who had not.Thirty-four patients were enrolled at 7 centers, with 32 completing the trial. There were 15 placebo and 17 steroid patients. There was no difference in survival, length of stay, duration of ventilation, or oxygen use at 30 days. For the cohort study, we looked at infants older than 34 weeks who were born after October 2000 when data on prenatal steroids were collected. There were 1093 patients; 390 were evaluable, with 56 receiving steroids. There was no difference in survival, length of stay, ventilator days, or oxygen use at 30 days.Neither the trial nor the CDH Registry suggest that late prenatal corticosteroids benefit fetuses with CDH. More than 1700 mothers and fetuses would need to be enrolled in a trial to show a 10% improvement in survival. It is unlikely that late steroids offer benefit to most fetuses with CDH.

Abstract

The appropriate determination of adequate tissue perfusion and the best approach to treatment of perceived abnormalities in blood pressure in the neonate remain controversial. There is no consensus regarding the actual definition of hypotension in the neonate or how best to raise perceived low blood pressure. In addition, there is no direct and prospectively collected information available on the result of treatment of a "low" blood pressure on neonatal morbidity and mortality. It also has not been clearly demonstrated that bringing systemic blood pressure to a "normal" range improve outcomes. However, it is widely accepted by clinicians that early and aggressive treatment of hypotension leads to improved neurologic outcome and survival in the neonate. Commonly used therapeutic maneuvers to correct systemic hypotension in the neonate include volume expansion, inotropic agents, and corticosteroids. Although there is a paucity of research on the cardiovascular response to these commonly used agents in neonates, among the commonly used inotropic drugs dopamine has been shown to be more effective than dobutamine in raising blood pressure in the neonate. The cardiology group focused on the use of inotropes, particularly dopamine and dobutamine, to treat very low birth weight infants with cardiac instability and neonatal postoperative cardiac patients. The cardiology group identified key issues that must be considered when designing studies of inotropic agents in preterm infants and proposed 2 clinical-trial designs: (1) a placebo-controlled trial with rescue for symptomatic infants; and (2) a targeted-blood pressure study. The first trial design would answer questions concerning efficacy of treatment with inotropic agents in this population. The second trial design would address concerns related to the lack of knowledge on normal blood pressure ranges in this population. The group identified specific design elements that would need to be addressed for the complicated trial design to study inotropic agents in neonates.

Abstract

Inhaled nitric oxide is a controversial treatment for premature infants with severe respiratory failure. We conducted a multicenter, randomized, blinded, controlled trial to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in such infants.We randomly assigned 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1500 g, and with respiratory failure more than four hours after treatment with surfactant to receive placebo (simulated flow) or inhaled nitric oxide (5 to 10 ppm). Infants with a response (an increase in the partial pressure of arterial oxygen of more than 10 mm Hg) were weaned according to protocol. Treatment with study gas was discontinued in infants who did not have a response.The rate of death or bronchopulmonary dysplasia was 80 percent in the nitric oxide group, as compared with 82 percent in the placebo group (relative risk, 0.97; 95 percent confidence interval, 0.86 to 1.06; P=0.52), and the rate of bronchopulmonary dysplasia was 60 percent versus 68 percent (relative risk, 0.90; 95 percent confidence interval, 0.75 to 1.08; P=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest that rates of death and bronchopulmonary dysplasia are reduced for infants with a birth weight greater than 1000 g, whereas infants weighing 1000 g or less who are treated with inhaled nitric oxide have higher mortality and increased rates of severe intracranial hemorrhage.The use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia. Further trials are required to determine whether inhaled nitric oxide benefits infants with a birth weight of 1000 g or more.

Abstract

Inhaled nitric oxide (iNO) is an effective adjunct in the treatment of infants with respiratory failure. Although there are clear benefits to this therapy, potential toxicity could result from reactive nitrosylated species.To evaluate whether iNO therapy is associated with increased serum markers of oxidative stress.Multiple markers were prospectively evaluated in the serum of term infants with severe respiratory failure treated with iNO for 1 to 72 hours. These were compared to those of patients exposed to greater than 80% oxygen for more than 6 hours and room air controls.After 24 hours of exposure, the iNO-treated infants had increased serum lipid hydroperoxides (LPO), protein carbonyls and nitrotyrosine residues as well as increased serum total glutathione (GSH) content. The increase in LPO peaked at 24 hours and correlated with the cumulative dose of iNO whereas other markers did not. The presence of chronic lung disease (CLD) did not correlate with serum markers of oxidative injury.In term infants with respiratory failure, prolonged iNO exposure is associated with a transient increase in markers of oxidative stress, but this finding does not appear to predict the development of CLD.

Abstract

Extracorporeal membrane oxygenation (ECMO) has been offered as a life-saving technology to newborns with respiratory and cardiac failure refractory to maximal medical therapy. ECMO has been used in treatment of neonates with a variety of cardio-respiratory problems, including meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the neonate (PPHN), congenital diaphragmatic hernia (CDH), sepsis/pneumonia, respiratory distress syndrome (RDS), air leak syndrome, and cardiac anomalies. For this group of high-risk neonates with an anticipated mortality rate of 80% to 85%, ECMO has an overall survival rate of 84%, with recent data showing nearly 100% survival in many diagnostic groups. This article reviews the current selection criteria for ECMO and the clinical management of neonates on ECMO, and discusses the long-term outcome of neonates treated with ECMO.

Abstract

Extracorporeal life support for neonatal respiratory failure has decreased, but utilization and outcome of cardiac extracorporeal life support are not well characterized. Among neonates born 1996-2000, our objects were to evaluate changes in utilization and outcome of cardiac extracorporeal life support and characterize correlates of survival.Retrospective analysis of Extracorporeal Life Support Organization Registry data.Intensive care units participating in the ELSO registry.Patients placed on extracorporeal life support for center-specified "cardiac support" at =30 days of age from 1996 to 2000. Patients with hypoplastic left heart syndrome were also analyzed separately.None.Patient characteristics and correlates of survival to discharge or transfer were analyzed by chi-square, Student's t-test, and logistic regression analysis. Neonates placed on cardiac extracorporeal life support increased from 112 in 1996 to 200 in 2000 (total n = 740). Overall survival was 34.2%: 28% for hypoplastic left heart syndrome and 35.4% for nonhypoplastic left heart syndrome. For the overall group, no significant correlations were found between survival and year on extracorporeal life support, multiple runs, or diagnosis of hypoplastic left heart syndrome. Diagnoses of transposition of the great arteries (p = .03) or persistent pulmonary hypertension of the neonate (p = .004) and extracorporeal life support at <3 days (p = .003) were associated with higher survival. Survivors had fewer mean extracorporeal life support hours (125.5 +/- 121.4 vs. 159.0 +/- 127.6, p = .0006). Logistic regression confirmed significant bivariate findings. A total of 118 hypoplastic left heart syndrome patients were reported from 1996 to 2000. Extracorporeal life support at >15 days was associated with improved survival among hypoplastic left heart syndrome patients (p = .03), and survivors had fewer mean extracorporeal life support hours (89.3 +/- 52.3 vs. 147.5 +/- 129.7, p = .015). Logistic regression showed that only greater number of hours on extracorporeal life support was independently associated with nonsurvival.Neonatal cardiac extracorporeal life support use increased substantially from 1996 to 2000, with survival to discharge or transfer in more than one third of patients. Hypoplastic left heart syndrome was not associated with nonsurvival. Fewer hours on extracorporeal life support, diagnoses of persistent pulmonary hypertension of the neonate and transposition of the great arteries, and extracorporeal life support at <3 days were associated with survival.

Abstract

Respiratory failure in neonates with congenital diaphragmatic hernia (CDH) may in part be caused by a primary or secondary surfactant deficiency. Knowledge of the optimal approach to surfactant replacement in neonates with CDH and respiratory failure is limited. The aim of this study was to determine if surfactant replacement on extracorporeal membrane oxygenation (ECMO) results in improved outcomes in neonates > or =35 weeks' gestation with unrepaired CDH.Using the CDH Study Group Registry, the authors identified 448 neonates with CDH who were > or =35 weeks' gestation, had no major anomalies, were treated with ECMO within the first 7 days of life, and underwent repair on or after ECMO therapy. Patients in 2 groups were compared: group 1 (- Surf, n = 334) consisted of patients who received no surfactant and group 2 (+ Surf, n = 114) consisted of patients who received at least 1 dose of surfactant while on ECMO. An analysis of all patients in both groups was performed. Additionally, subgroup analyses stratified by gestational age were performed for patients 351/7 to 366/7 weeks' gestation and for patients > or =37 weeks' gestation. Primary end-points for the study were survival and length of ECMO run. Secondary end-points were length of intubation, need for supplemental oxygen at 30 days of life, and at discharge to home. Demographic, clinical, and outcome variables were examined using Fisher's Exact tests for categorical variables and using unpaired t tests for continuous variables. Odds ratios were calculated for categorical end-point variables.Demographic and clinical variables were similar between groups. Analyses of aggregate data showed no significant differences between groups in length of ECMO run, survival, number of days intubated, and percent of patients requiring supplemental oxygen at 30 days or discharge. Subgroup stratification by gestational age did not show significant differences between groups in any of the outcome variables.The data from this study suggest that surfactant replacement on ECMO for neonates with congenital diaphragmatic hernia does not provide significant benefit in the infant's clinical course with respect to survival, length of ECMO course, length of intubation, or subsequent need for supplemental oxygen.

Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia?JOURNAL OF PEDIATRICSVan Meurs, K.2004; 145 (3): 312-316

Abstract

To determine the impact of surfactant replacement on survival, need for extracorporeal membrane oxygenation (ECMO), and chronic lung disease in term infants with prenatally diagnosed congenital diaphragmatic hernia (CDH).Prenatally diagnosed infants born at > or =37 weeks' gestation with immediate distress at delivery and no other major congenital anomalies, who were enrolled in the CDH Registry, were analyzed. For univariate analysis, chi 2 tests were used for categoric variables and unpaired t tests for nominal variables. Multiple logistic regression was used to calculate adjusted odds ratios.Eligible infants (n = 522) were identified. Demographic variables were similar between the surfactant-treated (n = 192) and nonsurfactant-treated (n = 330) groups, with the exception of race (white, 88.0% vs 71.2%; P =.0007). The use of ECMO and incidence of chronic lung disease were higher (59.8 vs 50.6, P =.04; 59.9 vs 47.6, P =.0066) and survival lower in the surfactant-treated cohort (57.3 vs 70.0, P =.0033). Adjusted logistic regression for use of ECMO, survival, and chronic lung disease resulted in odds ratios inconsistent with an improved outcome associated with surfactant use.This analysis shows no benefit associated with surfactant therapy for term infants with a prenatal diagnosis of isolated CDH.

Abstract

Use of exogenous surfactant in congenital diaphragmatic hernia (CDH) patients is routine in many centers. The authors sought to determine the impact of surfactant use in the premature infant with CDH.Data on liveborn infants with CDH from participating institutions were collected prospectively. Surfactant use and timing and outcome data were analyzed retrospectively. The authors evaluated the prenatal diagnosis patients as well. The outcome variable was survival to discharge. Odds ratios with confidence intervals were calculated.Five hundred ten infants less than 37 weeks' gestation were entered in the CDH registry. Infants with severe anomalies (n = 80) were excluded. Information on surfactant use was available for 424 patients. Infants receiving surfactant (n = 209) had a greater odds of death than infants not receiving surfactant (n = 215, odds ratio, 2.17, 95% CI: 1.5 to 3.2; P

Abstract

Inhaled nitric oxide (iNO) reduces the use of extracorporeal membrane oxygenation (ECMO)/incidence of death in term and near-term neonates with severe hypoxic respiratory failure. We conducted a randomized, double masked, multicenter trial to determine whether administration of iNO earlier in respiratory failure results in additional reduction in the incidence of these outcomes.Neonates who were born at > or =34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) > or =15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy.The trial enrollment was halted after 75% of target sample size was reached because of decreasing availability of eligible patients. The 150 infants who were given early iNO and 149 control infants had similar baseline characteristics. Arterial oxygen tension increased by >20 mm Hg in 73% of early iNO and 37% of control infants after study gas initiation. Control infants received standard iNO and deteriorated to OI >40 more often than infants who were given early iNO. The incidence of death (early iNO, 6.7% vs control, 9.4%), ECMO (10.7% vs 12.1%), and their combined incidence (16.7% vs 19.5%) were similar in both groups.iNO improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure.

Abstract

Extracorporeal membrane oxygenation (ECMO) therapy requires that patients be anticoagulated to prevent clotting and thrombotic complications. There are several bedside whole blood microcoagulation systems available to determine activated clotting time (ACT) levels. Many ECMO centers use Hemochron (International Technidyne, Edison, NJ) products to determine ACT levels. During the study period, we used the Hemochron 400 and then changed to the Hemochron Junior Low Range. There were two specific aims of this study. First, to determine if there was a difference in ACT levels measured by these two distinct Hemochron products both marketed for the use in ECMO therapy. Second, to determine if the differing ACT levels produced by these two devices affected clinical outcomes. We compared ACT levels between two devices on 70 paired blood specimens obtained from four neonatal ECMO patients receiving heparin. A retrospective review of 77 ECMO patients was performed to analyze frequency of circuit emergencies and length of ECMO circuit life while using the two products. In lower ACT ranges, the Hemochron Jr. LR consistently yielded higher ACT values than the Hemochron 400. In higher ACT ranges, the Hemochron Jr. LR consistently yielded lower ACT values than the Hemochron 400. Without calibration, after changing devices, this discrepancy led to shorter circuit life and more circuit clotting complications. After calibration and adjustment in target ACT values, there was a trend toward longer circuit life, and there were fewer clotting complications. There is a difference in the ACT values produced by Hemochron 400 and Hemochron Jr. LR. Failure to calibrate target ACT levels after changing machines may lead to shorter circuit life and more clotting complications.

Abstract

Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) traditionally has been the mode of support used in congenital diaphragmatic hernia (CDH). A few studies report success using venovenous (VV) ECMO. The purpose of this study is to compare outcomes in CDH patients treated with VA and VV.The authors queried the Extracorporeal Life Support Organization Registry for newborns with CDH treated with ECMO from January 1, 1990 through December 31, 1999. They analyzed the pre-ECMO data, ECMO course, and complications.VA was utilized in 2,257 (86%) and VV in 371 (14%) patients. The pre-ECMO status was similar, with greater use of nitric oxide, surfactant, and pressors in VV. Survival rate was similar (58.4% for VV and 52.2% for VA, P =.057). VA was associated with more seizures (12.3% v 6.7%, P =.0024) and cerebral infarction (10.5% v 6.7%, P =.03). Sixty-four treatments were converted from VV to VA (VV-->VA). Survival rate in VV-->VA was not significantly different than VA (43.8% v 52.2%, respectively; P =.23). VV-->VA and VA patients had similar neurologic complications.CDH patients treated with VV and VA have similar survival rates. VA had more neurologic complications. The authors identified no disadvantage to the use of VV as an initial mode of ECMO for CDH, although some infants may need conversion to VA.

Abstract

To evaluate the feasibility of conducting a prospective, randomized trial comparing early high-frequency oscillatory ventilation (HFOV) to synchronized intermittent mandatory ventilation (SIMV) in very low birth weight (VLBW) premature infants. This pilot study evaluated two ventilator management protocols to determine how well they could be implemented in a multicenter clinical trial. Although this pilot study was not powered to detect differences in outcome, we also collected outcome data.Prospective, multicenter, randomized pilot study.Seven tertiary-level intensive care nurseries with previous experience with both HFOV and flow-triggered SIMV.Fifty infants weighing 501 to 1200 g, less than 4 hours of age, who had received one dose of surfactant and required ventilation with mean airway pressure > or =6 cm H2O and F(I)O2 > or =0.25, and had an anticipated duration of ventilation greater than 24 hours.Patients were stratified by birth weight and prenatal steroid status, then randomized to either HFOV or SIMV with tidal volume monitoring. Ventilator management for patients in both study arms was strictly governed by protocols that included optimizing lung inflation and blood gases, weaning strategies, and extubation criteria.Data were collected using the tools planned for the larger collaborative study. Protocol compliance was closely monitored, with successive changes in the protocol made as necessary to improve clarity and increase compliance. The incidence of major neonatal adverse outcomes was recorded.Data are presented for 24 HFOV and 24 SIMV infants (two infants, twins, were withdrawn from the study at parent's request). Nineteen of the 24 HFOV infants and 20 of the 24 SIMV infants survived to 36 weeks corrected age. Age at final extubation for survivors was 16+/-16 (mean+/-SD) days for HFOV infants and 24+/-24 days for SIMV infants. At 36 weeks corrected age, 14 of the 19 HFOV survivors were extubated and in room air, whereas 5 required supplemental oxygen. In comparison, 6 of the 20 SIMV survivors were extubated and in room air, whereas 14 required supplemental oxygen. Grade III/IV IVH and/or periventricular leukomalacia occurred in 2 HFOV and 2 SIMV patients. Overall compliance with the ventilator protocols was 82% for the SIMV protocol, and 88% for the HFOV protocol.The preliminary outcome data supports conducting the large randomized trial, which began in July of 1998. The protocols for the ventilator management of VLBW infants, both with HFOV and with SIMV were easily implemented and consistently followed, and are presented here.

Abstract

Over the last decade, several new therapies, including high-frequency oscillatory ventilation (HFOV), exogenous surfactant therapy, and inhaled nitric oxide (iNO), have become available for the treatment of neonatal hypoxemic respiratory failure. The purpose of this retrospective study was to ascertain to what extent these modalities have impacted the use of neonatal extracorporeal membrane oxygenation (ECMO) at our institution.Patients from 2 time periods were evaluated: May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2). During the first time period (group 1), HFOV was not consistently used; beractant (Survanta) use for meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia was under investigation; and iNO was not yet available. During the second time period (group 2), HFOV and beractant treatment were considered to be standard therapies, and iNO was available to patients with oxygenation index (OI) >/=25 x 2 at least 30 minutes apart, or on compassionate use basis. Patients were included in the data collection if they met the following entry criteria: 1) OI >15 x 1 within the first 72 hours of admission; 2) EGA >/=35 weeks; 3) diagnosis of MAS, PPHN or sepsis/pneumonia; 4) <5 days of age on admission; and 5) no congenital heart disease, diaphragmatic hernia, or lethal congenital anomaly.Of the 49 patient in group 1, 21 (42.8%) required ECMO therapy. Of these ECMO patients, 14 (66.6%) had received diagnoses of MAS or PPHN. Only 3 of the patients that went on to ECMO received beractant before the initiation of bypass (14.3%). All ECMO patients in group 1 would have met criteria for iNO had it been available. Of all patients in group 1, 18 (36.7%) were treated with HFOV, and 13 (26.5%) received beractant. Of the 47 patients in group 2, only 13 (27.7%) required ECMO therapy (compared with group 1). Of these ECMO patients, only 5 (38.5%) had diagnoses of MAS or PPHN, with the majority of patients (61.5%) requiring ECMO for sepsis/pneumonia, with significant cardiovascular compromise. Only 5 of these ECMO patients, all outborn, did not receive iNO before cannulation because of the severity of their clinical status on admission. Of all patients in group 2, 41 (87.2%) were treated with HFOV (compared with group 1), 42 (89.3%) received beractant (compared with group 1), and 18 (44.7%) received iNO.The results indicate that ECMO was used less frequently when HFOV, beractant and iNO was more commonly used. The differences in treatment modalities used and subsequent use of ECMO were statistically significant. We speculate that, in this patient population, the diagnostic composition of neonatal ECMO patients has changed over time.

Abstract

Primary infection in the neonate, especially group B streptococcal infection, has long been recognized as a cause of persistent pulmonary hypertension of the newborn (PPHN), sometimes requiring treatment with inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO). However, secondary nosocomial infections in the neonatal period have not been widely reported as a cause of severe recurrent pulmonary hypertension (PHTN). We now present two cases of secondary infection in the neonate leading to significant PHTN. In both cases, the infants presented with PPHN soon after birth, requiring transfer to a level 3 neonatal intensive care unit and treatment with high-frequency oscillatory ventilation and iNO. After successful resolution of the initial PPHN, including extubation to nasal cannula, both infants developed signs of severe recurrent PHTN, leading to reintubation, high-frequency oscillatory ventilation and iNO therapy, and consideration of ECMO. In both cases, blood cultures taken at the time of recurrence of PHTN returned positive, one for Staphylococcus epidermidis, the other for methicillin-resistant Staphylococcus aureus. These unusual cases present the possibility of severe recurrent PHTN requiring iNO or ECMO in the setting of secondary infection. We speculate that these infants, although extubated after their first episodes of PHTN, were at risk for recurrence of PHTN due to continued pulmonary vascular reactivity.

Abstract

Inhaled nitric oxide (INO) improved oxygenation and reduced the occurrence of death or extracorporeal membrane oxygenation in term and near-term hypoxic neonates. We report the results of neurodevelopmental follow-up of infants enrolled in the NINOS trial.Hypoxic infants >/=34 weeks' gestation and <14 days of age were randomized to 20 ppm INO or 100% oxygen as control. Comprehensive neurodevelopmental assessment of survivors occurred at 18 to 24 months of age.A total of 235 infants were enrolled in the original trial. There were 36 deaths, 20 of 121 infants in the control group and 16 of 114 infants in the INO-treated group. Of the 199 surviving infants, 173 (86.9%) were seen for follow-up (88 members of the control group and 85 members of the INO-treated group), and 135 infants were normal (69 [79.3%] members of the control group and 66 [77.6%] members of the INO-treated group). Twenty-two infants had sensorineural hearing loss (12 members of the control group and 10 members of the INO-treated group). Moderate to severe cerebral palsy occurred in 13 infants (7 infants in the control group and 6 infants in the INO-treated group). Mental developmental index scores (87 +/- 18.7 in the control group vs 85 +/- 21.7 in the INO-treated group) and psychomotor developmental index scores (93.6 +/- 17.5 in the control group vs 85.7 +/- 21.2 in the INO-treated group) were not different. A total of 29.6% of the control group compared with 34.5% of the INO-treated group had at least one disability. Infants with congenital diaphragmatic hernia, enrolled in a separate but parallel trial, had similar outcomes with a higher incidence of sensorineural hearing loss.Inhaled nitric oxide is not associated with an increase in neurodevelopmental, behavioral, or medical abnormalities at 2 years of age.

Abstract

Nitrogen dioxide (NO2) is a toxic by-product of inhalation therapy with nitric oxide (NO). The rate of NO2 formation during NO therapy is controversial.The formation of NO2 was studied under dynamic flows emulating a base case NO ventilator mixture containing 80 ppm NO in a 90% oxygen matrix. The difficulty in measuring NO2 concentrations below 2 ppm accurately was overcome by the use of tunable diode laser absorption spectroscopy.Using a second-order model, the rate constant, k, for NO2 formation was determined to be (1.19 +/- 0.11) x 10(-11) ppm-2s-1, which is in basic agreement with evaluated data from atmospheric literature.Inhaled NO can be delivered safely in a well-designed, continuous flow neonatal ventilatory circuit, and NO2 formation can be calculated reliably using the rate constant and circuit dwell time.

Abstract

Elevated pulmonary vascular resistance is seen in premature infants with severe respiratory distress syndrome (RDS). Inhaled nitric oxide (NO) has been shown to decrease pulmonary vascular resistance and to improve oxygenation in some patients with respiratory failure. The purpose of this study was to determine whether premature infants with severe RDS would respond to inhaled NO with an improvement in oxygenation. Eleven premature infants (mean gestational age 29.8 weeks) with severe respiratory failure caused by RDS were treated with NO in four concentrations [1, 5, 10, 20 parts per million (ppm) NO] and with placebo (0 ppm NO). Arterial blood gas measurements were drawn immediately before and at the end of each of the 15-minute treatments and were used to determine the arterial/alveolar oxygen ratio (PaO2/PAO2). Ten of the 11 infants had a greater than 25% increase in PaO2/PAO2. Five of the 11 had a greater than 50% increase in PaO2/PAO2. Despite normal cranial ultrasound imaging prior to NO, 3 infants had intracranial hemorrhage (ICH) noted on their first ultrasound scan after this brief period of NO treatment, and 4 additional infants developed ICH later during their hospitalization. No infant had significant elevations of methemoglobin concentrations after the total 60-minute exposure to NO. NO may be an effective method of improving oxygenation in infants with severe RDS. The disturbing incidence of ICH in this small group of infants needs to be carefully evaluated before considering routine use or NO for preterm infants.

Abstract

We report the clinical course and successful surgical treatment of hemopericardium resulting from coronary artery (CA) laceration in two patients with congenital diaphragmatic hernia (CDH) undergoing extracorporeal membrane oxygenation (ECMO) bypass.Retrospective case review.Two neonates with CDH had needle aspiration for either pneumothorax or pericardial effusion before initiation of ECMO. While on bypass, progressive hemopericardium led to narrow pulse pressure and decreased venous return that limited bypass flow. Widened cardiac silhouette on chest radiographs suggested hemopericardium; echocardiography was confirmatory in one case. The underlying diagnosis of CA laceration was made during pericardiotomy and treated with surgical patching.Pre-ECMO history of cardiothoracic needle aspiration is important because complications such as hemothorax or hemopericardium may arise once ECMO bypass is initiated. Inadvertent CA laceration may lead to acute hemopericardium, compromising venous drainage. However, CA laceration can be successfully repaired while the patient is on bypass.

Abstract

Sengers' syndrome is a rare condition consisting of congenital cataracts, mitochondrial myopathy, and hypertrophic cardiomyopathy. The syndrome is transmitted in an autosomal recessive pattern. Progressive cardiac failure is the cause of death in most patients. This report describes cardiac transplantation for the treatment of the cardiomyopathy associated with Sengers' syndrome.

Abstract

Because the effects of inhaled nitric oxide (NO) may be localized to its site of delivery, we studied the effects of inhaled NO on the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension in perfused rabbit lungs. Before NO administration, pulmonary hypertension was produced by infusion of the thromboxane A2 mimetic U-46619 in all lungs. Pulmonary vascular resistance was divided into arterial, microvascular, and venous components by arterial and venous occlusion techniques. In the buffer-perfused lung, all doses of inhaled NO (5, 20, and 80 ppm) produced small decreases (approximately 3 mmHg) in pulmonary arterial pressure (Ppa), with equivalent proportional reductions in all segmental vascular resistances. Similar results were obtained after an extended inhaled NO dose range of 20, 80, and 240 ppm. In the buffer-perfused lung, inhibition of endogenous NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) potentiated the effects of U-46619. Subsequent inhaled NO administration produced larger decreases (approximately 7 mmHg) in Ppa with equivalent proportional reductions in all segmental vascular resistances. In the blood-perfused lung, L-NAME did not alter baseline pulmonary pressures. Administration of inhaled NO during U-46619-induced pulmonary hypertension produced dose-related decreases in Ppa. The highest dose (80 ppm) of inhaled NO decreased Ppa by 3.5 mmHg, with equivalent proportional reductions in all segmental vascular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

The mortality rate for infants severely affected with congenital diaphragmatic hernia (CDH) remains high despite significant advances in surgical and neonatal intensive care including delayed repair and extracorporeal membrane oxygenation (ECMO). Because of the increasingly successful experience with single-lung transplantation in adults; this approach has been suggested as a potential treatment for CDH infants with unsalvageable pulmonary hypoplasia. The authors report on a newborn female infant who was the product of a pregnancy complicated by polyhydramnios. At birth, she was found to have a right-sided CDH and initially was treated with preoperative ECMO, followed by delayed surgical repair. Despite the CDH repair and apparent resolution of pulmonary hypertension, the infant's condition deteriorated gradually after decannulation, and escalating ventilator settings were required as well as neuromuscular paralysis and pressor support because of progressive hypoxemia and hypercarbia. A lung transplant was performed 8 days after decannulation, using the right lung obtained from a 6-week-old donor. The right middle lobe was excised because of the size discrepancy between the donor and recipient. After transplantation, the patient was found to have duodenal stenosis and gastroesophageal reflux, which required duodenoduodenostomy and fundoplication. The patient was discharged from the hospital 90 days posttransplantation, at 3 1/2 months of age. Currently she is 24 months old and doing well except for poor growth. This case shows the feasibility of single-lung transplantation for infants with CDH, and the potential use of ECMO as a temporary bridge to transplantation. Lobar lung transplantation allowed for less stringent size constraints for the donor lung.

Abstract

Computed tomography scans of the head and early neurodevelopmental assessment (Bayley Scales of Infant development) were recorded for 24 surviving infants who received venovenous extracorporeal membrane oxygenation and were compared with those of infants treated with venoarterial bypass matched by diagnosis and oxygenation index before extracorporeal membrane oxygenation. A comparable neuroradiographic and early neurodevelopmental outcome was documented for survivors of venoarterial and venovenous extracorporeal membrane oxygenation.

Abstract

As more infants with congenital diaphragmatic hernia (CDH) survive with extracorporeal membrane oxygenation (ECMO), it seems prudent to detail the longterm outcome in these medically complex infants. Eighteen children with CDH-treated with postoperative ECMO were recruited for participation in this study. The mean duration of ECMO was 193 hours (range 82 to 493 hours), mean time to extubation after ECMO was 142 hours (range 34 to 312 hours), and median duration of hospitalization was 46 days (range 30 to 181 days). Of the 18 infants, 4 (22%) were discharged home requiring oxygen therapy. At follow-up the notable findings were a high incidence of gastroesophageal reflux and failure to thrive. At both 1 and 2 years of age, 50% of infants were at less than the 5th percentile for weight. At 1 and 2 years of age, 39% and 21%, respectively, were at less than the 5th percentile for weight/length ratio. A total of 16 children (89%) had clinical evidence of reflux, and 8 (44%) were discharged home on a regimen of nasogastric feedings. Reherniation occurred in 4 children (22%) and was more frequent when a patch was used. An electrocardiogram showed right ventricular hypertrophy in 6 (43%); oxygen saturation by pulse oximetry was > 95% in all children, and pulmonary artery pressure was estimated by Doppler echocardiography to be normal in 12 of 14 children examined. The neurodevelopmental outcome (Bayley Scales or Stanford-Binet scale) at 1 to 4 years of age was not dissimilar from that of other ECMO-treated children. Given the severity of illness in the neonatal period, the general health and development of children with CDH surviving after ECMO are good. Surprisingly few children have long-term respiratory complications related to pulmonary hypoplasia. Follow-up in the first few years should be aimed at aggressive nutritional intervention to prevent the growth failure that appears to be prevalent in these children.

Abstract

To determine the effect of extracorporeal membrane oxygenation (ECMO) on the survival of infants with congenital diaphragmatic hernia, we undertook a retrospective review of 31 infants with congenital diaphragmatic hernia treated at Children's National Medical Center. Infants were categorized by means of the Bohn quadrant analysis to determine the impact of ECMO on infants with congenital diaphragmatic hernia and a "poor prognosis." All infants assigned to the Bohn 100% mortality quadrant required ECMO. The survival rate in this group was 86% (6/7) when assessed preoperatively and 67% (6/9) when assessed postoperatively. Comparison of the change occurring in ventilation index and arterial carbon dioxide pressure demonstrated that after repair the clinical condition of 48% of infants deteriorated, 40% improved, and 12% remained unchanged. Of the 12 infants whose condition was worse after surgery, 11 eventually required ECMO. Our review demonstrates that ECMO improved survival significantly in infants with congenital diaphragmatic hernia who had a "poor prognosis" by the criteria of Bohn et al. We recommend consideration of ECMO for all infants with congenital diaphragmatic hernia for whom maximal medical therapy has failed.

Abstract

Mortality in infants with congenital diaphragmatic hernia (CDH) remains high despite improvements in neonatal and surgical care because many infants develop persistent pulmonary hypertension of the newborn (PPHN) following repair. Since 1984, extracorporeal membrane oxygenation (ECMO) has been used as rescue therapy in all infants (n = 25) with PPHN following CDH repair when conventional management failed, with an overall survival of 60%. Repair was performed in this hospital on 12 infants and in other hospitals in 13 infants transferred for consideration of ECMO after repair. Mortality was the same in the group repaired here and those transferred for ECMO. Although complications were frequent in the surviving group, they were successfully managed with nonoperative or operative therapy. Selective use of ECMO has been advocated in CDH patients based on various predictors of high mortality such as "best" PO2 postrepair less than 100 mm Hg, oxygenation index greater than 40, and ventilation index greater than 1,000 with PCO2 greater than 40. Seven surviving infants following ECMO would have been classified as unsalvageable by at least one parameter if selection criteria based on these parameters had been used. We conclude from this series that current predictors of high mortality in CDH patients are unreliable when ECMO is used. Surgeons caring for infants with CDH should consider the use of ECMO in all infants.

Abstract

The arterial cannulae used in neonatal ECMO cause hemolysis and red blood cell damage at elevated blood flows. Hemolysis in extracorporeal circuits has been found to occur with shear stress greater than 132 dynes/cm2, turbulence as measured by Reynold's number greater than 1,000, and velocity greater than 120 to 200 cm/sec. These parameters need to be considered when sizing the proper arterial cannula for a required flow rate. In-vitro measurements of the pressure drop across six arterial cannulae at varying flow rates were performed using human blood with a hematocrit of 43%. Shear stress, Reynold's number, velocity, and pressure drop were calculated for each catheter at flow rates from 50 to 1,000 cc/min. The maximum mean flow rate to maintain the shear stress, Reynold's number, velocity, and pressure drop within the accepted range, was determined for each cannula. Recommended maximum blood flow rates for each of the six cannulae are given. Internal diameter, length, and cannula geometry appear to be the factors most affecting the flow achievable without causing red blood cell damage and hemolysis. Ten French Biomedicus, 10 French Cook, and 10 French Elecath arterial cannulae appear best suited to deliver the range of blood flow rates used in neonatal ECMO.

Abstract

Go, a guanine nucleotide binding protein found predominantly in neural tissues, interacts in vitro with rhodopsin, muscarinic, and other receptors and has been implicated in the regulation of ion channels. Despite the virtual identity of reported cDNA sequences for the alpha subunit of Go (Go alpha), multiple molecular weight forms of mRNA have been identified in tissues from all species examined. To investigate the molecular basis for the size heterogeneity of Go alpha mRNAs, four cDNA clones were isolated from the same retinal lambda gt10 cDNA library that was used earlier to isolate lambda GO9, a clone encompassing the complete coding region of Go alpha. These clones were identified as Go alpha clones based on nucleotide sequence identity with lambda GO9 in the coding region; they diverge, however, from lambda GO9 in the 3'-untranslated region 28 nucleotides past the stop codon. An oligonucleotide probe complementary to a portion of the 3'-untranslated region of lambda GO9 that differs from the newly isolated clones hybridized with 3.0- and 4.0-kb mRNAs present in bovine brain and retina whereas a similar probe for the unique region of the new clones hybridized with a 4.0-kb mRNA in both tissues and with a 2.0-kb mRNA found predominantly in retina. A similar hybridization pattern was observed when brain poly(A+) RNA from other species was hybridized with the different 3'-untranslated region probes. It appears that differences in the 3'-untranslated regions could, in part, be the basis for the observed heterogeneity in Go alpha mRNAs.

IDENTIFICATION OF THE PROBABLE SITE OF CHOLERAGEN-CATALYZED ADP-RIBOSYLATION IN A GO-ALPHA-LIKE PROTEIN BASED ON CDNA SEQUENCEPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAAngus, C. W., VanMeurs, K. P., Tsai, S. C., Adamik, R., MIEDEL, M. C., Pan, Y. C., Kung, H. F., Moss, J., Vaughan, M.1986; 83 (16): 5813-5816

Abstract

Go alpha, a 39-kDa guanyl nucleotide-binding protein, is functionally and structurally similar to the alpha subunits of the stimulatory and inhibitory guanyl nucleotide-binding proteins (Gs alpha, Gi alpha) of adenylate cyclase and to the alpha subunit of transducin (T alpha), the guanyl nucleotide-binding protein of the retinal photon reception system. A cDNA clone was isolated from a bovine retinal lambda gt10 library by using oligonucleotide probes complementary to sequences in two putative T alpha clones. Partial sequence analysis revealed a deduced amino acid sequence identical to sequences of four tryptic peptides from bovine brain Go alpha. Gs alpha and T alpha are known to serve as substrates for ADP-ribosylation by choleragen. Other workers have established the sequence of the tetrapeptide in T alpha containing the arginine that is ADP-ribosylated and its location in the amino acid sequence deduced from T alpha cDNA. The Go alpha cDNA described here includes a region encoding an amino acid sequence very similar to that surrounding the ADP-ribosylation site in T alpha, consistent with observations that Go alpha can also be a substrate for choleragen. A corresponding sequence in the recently identified Gs alpha cDNA is less homologous to that in T alpha or Go alpha. The reported differences in conditions that promote choleragen-catalyzed ADP-ribosylation of Gs alpha vs. Go alpha could be related to differences in amino acid sequence in the region of the acceptor arginine.